Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization

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} div.type-section h2 { font-size: 20px; line-height: 26px; font-weight: 300; } div.type-section h3 { margin-left: 15px; margin-bottom: 0px; font-weight: 300; } .journal-tabs .tab-title.active a { } </style> <link rel="stylesheet" href="https://pub.mdpi-res.com/assets/css/slick.css?f38b2db10e01b157?1732286508"> <meta name="title" content="Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization"> <meta name="description" content="Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biologicalactivity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilicsubstitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activityrelationships could be derived. Optimization was successful, leading to 3g, identfied as themost potent compound (69 % inhibition). Experiments with viral particles revealed thatthere might be additional HCV infection reducing mechanisms." > <link rel="image_src" href="https://pub.mdpi-res.com/img/journals/molecules-logo.png?8600e93ff98dbf14" > <meta name="dc.title" content="Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization"> <meta name="dc.creator" content="Marcel Holzer"> <meta name="dc.creator" content="Sigrid Ziegler"> <meta name="dc.creator" content="Beatrice Albrecht"> <meta name="dc.creator" content="Bernd Kronenberger"> <meta name="dc.creator" content="Artur Kaul"> <meta name="dc.creator" content="Ralf Bartenschlager"> <meta name="dc.creator" content="Lars Kattner"> <meta name="dc.creator" content="Christian D. Klein"> <meta name="dc.creator" content="Rolf W. Hartmann"> <meta name="dc.type" content="Article"> <meta name="dc.source" content="Molecules 2008, Vol. 13, Pages 1081-1110"> <meta name="dc.date" content="2008-05-07"> <meta name ="dc.identifier" content="10.3390/molecules13051081"> <meta name="dc.publisher" content="Molecular Diversity Preservation International"> <meta name="dc.rights" content="http://creativecommons.org/licenses/by/3.0/"> <meta name="dc.format" content="application/pdf" > <meta name="dc.language" content="en" > <meta name="dc.description" content="Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biologicalactivity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilicsubstitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activityrelationships could be derived. Optimization was successful, leading to 3g, identfied as themost potent compound (69 % inhibition). Experiments with viral particles revealed thatthere might be additional HCV infection reducing mechanisms." > <meta name="dc.subject" content="Hepatitis C Virus" > <meta name="dc.subject" content="CD81-receptor" > <meta name="dc.subject" content="large extracellular loop" > <meta name="dc.subject" content="terfenadine derivatives" > <meta name="dc.subject" content="microwave assisted syntheses." > <meta name ="prism.issn" content="1420-3049"> <meta name ="prism.publicationName" content="Molecules"> <meta name ="prism.publicationDate" content="2008-05-07"> <meta name ="prism.volume" content="13"> <meta name ="prism.number" content="5"> <meta name ="prism.section" content="Article" > <meta name ="prism.startingPage" content="1081" > <meta name ="prism.endingPage" content="1110" > <meta name="citation_issn" content="1420-3049"> <meta name="citation_journal_title" content="Molecules"> <meta name="citation_publisher" content="Molecular Diversity Preservation International"> <meta name="citation_title" content="Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization"> <meta name="citation_publication_date" content="2008/5"> <meta name="citation_online_date" content="2008/05/07"> <meta name="citation_volume" content="13"> <meta name="citation_issue" content="5"> <meta name="citation_firstpage" content="1081"> <meta name="citation_author" content="Holzer, Marcel"> <meta name="citation_author" content="Ziegler, Sigrid"> <meta name="citation_author" content="Albrecht, Beatrice"> <meta name="citation_author" content="Kronenberger, Bernd"> <meta name="citation_author" content="Kaul, Artur"> <meta name="citation_author" content="Bartenschlager, Ralf"> <meta name="citation_author" content="Kattner, Lars"> <meta name="citation_author" content="Klein, Christian D."> <meta name="citation_author" content="Hartmann, Rolf W."> <meta name ="citation_lastpage" content="1110" > <meta name="citation_doi" content="10.3390/molecules13051081"> <meta name="citation_id" content="mdpi-13051081"> <meta name="citation_abstract_html_url" content="https://www.mdpi.com/1420-3049/13/5/1081"> <meta name="citation_pdf_url" content="https://www.mdpi.com/1420-3049/13/5/1081/pdf?version=1403112490"> <link rel="alternate" type="application/pdf" title="PDF Full-Text" href="https://www.mdpi.com/1420-3049/13/5/1081/pdf?version=1403112490"> <meta name="fulltext_pdf" content="https://www.mdpi.com/1420-3049/13/5/1081/pdf?version=1403112490"> <meta name="citation_fulltext_html_url" content="https://www.mdpi.com/1420-3049/13/5/1081/htm"> <link rel="alternate" type="text/html" title="HTML Full-Text" href="https://www.mdpi.com/1420-3049/13/5/1081/htm"> <meta name="fulltext_html" content="https://www.mdpi.com/1420-3049/13/5/1081/htm"> <link rel="alternate" type="text/xml" title="XML Full-Text" href="https://www.mdpi.com/1420-3049/13/5/1081/xml"> <meta name="fulltext_xml" content="https://www.mdpi.com/1420-3049/13/5/1081/xml"> <meta name="citation_xml_url" content="https://www.mdpi.com/1420-3049/13/5/1081/xml"> <meta name="twitter:card" content="summary" /> <meta name="twitter:site" content="@MDPIOpenAccess" /> <meta name="twitter:image" content="https://pub.mdpi-res.com/img/journals/molecules-logo-social.png?8600e93ff98dbf14" /> <meta property="fb:app_id" content="131189377574"/> <meta property="og:site_name" content="MDPI"/> <meta property="og:type" content="article"/> <meta property="og:url" content="https://www.mdpi.com/1420-3049/13/5/1081" /> <meta property="og:title" content="Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization" /> <meta property="og:description" content="Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-tert-butylphenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27% inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biologicalactivity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilicsubstitution. The prepared compounds were tested for their inhibitory potency by means ofa fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activityrelationships could be derived. Optimization was successful, leading to 3g, identfied as themost potent compound (69 % inhibition). Experiments with viral particles revealed thatthere might be additional HCV infection reducing mechanisms." /> <meta property="og:image" content="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001-550.jpg?1553234365" /> <link rel="alternate" type="application/rss+xml" title="MDPI Publishing - Latest articles" href="https://www.mdpi.com/rss"> <meta name="google-site-verification" content="PxTlsg7z2S00aHroktQd57fxygEjMiNHydKn3txhvwY"> <meta name="facebook-domain-verification" content="mcoq8dtq6sb2hf7z29j8w515jjoof7" /> <script id="Cookiebot" data-cfasync="false" src="https://consent.cookiebot.com/uc.js" data-cbid="51491ddd-fe7a-4425-ab39-69c78c55829f" type="text/javascript" async></script>  <script type="text/plain" data-cookieconsent="statistics"> (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f); 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class='html-article-content'> <span itemprop="publisher" content="Molecular Diversity Preservation International"></span><span itemprop="url" content="https://www.mdpi.com/1420-3049/13/5/1081"></span> <div class="article-icons"><span class="label openaccess" data-dropdown="drop-article-label-openaccess" aria-expanded="false">Open Access</span><span class="label articletype">Article</span></div> <h1 class="title hypothesis_container" itemprop="name"> Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization </h1> <div class="art-authors hypothesis_container"> by <span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5588' data-options='is_hover:true, hover_timeout:5000'> Marcel Holzer</div><div id="profile-card-drop5588" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Marcel Holzer </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Marcel%20Holzer" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Marcel%20Holzer&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Marcel%20Holzer" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5589' data-options='is_hover:true, hover_timeout:5000'> Sigrid Ziegler</div><div id="profile-card-drop5589" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Sigrid Ziegler </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Sigrid%20Ziegler" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Sigrid%20Ziegler&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Sigrid%20Ziegler" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5590' data-options='is_hover:true, hover_timeout:5000'> Beatrice Albrecht</div><div id="profile-card-drop5590" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Beatrice Albrecht </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Beatrice%20Albrecht" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Beatrice%20Albrecht&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Beatrice%20Albrecht" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5591' data-options='is_hover:true, hover_timeout:5000'> Bernd Kronenberger</div><div id="profile-card-drop5591" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Bernd Kronenberger </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Bernd%20Kronenberger" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Bernd%20Kronenberger&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Bernd%20Kronenberger" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5592' data-options='is_hover:true, hover_timeout:5000'> Artur Kaul</div><div id="profile-card-drop5592" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Artur Kaul </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Artur%20Kaul" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Artur%20Kaul&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Artur%20Kaul" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 2</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5593' data-options='is_hover:true, hover_timeout:5000'> Ralf Bartenschlager</div><div id="profile-card-drop5593" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Ralf Bartenschlager </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Ralf%20Bartenschlager" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Ralf%20Bartenschlager&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Ralf%20Bartenschlager" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 2</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5594' data-options='is_hover:true, hover_timeout:5000'> Lars Kattner</div><div id="profile-card-drop5594" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Lars Kattner </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Lars%20Kattner" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Lars%20Kattner&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Lars%20Kattner" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 3</sup>, </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5595' data-options='is_hover:true, hover_timeout:5000'> Christian D. Klein</div><div id="profile-card-drop5595" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"> Christian D. Klein </div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://scilit.net/scholars?q=Christian%20D.%20Klein" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Christian%20D.%20Klein&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Christian%20D.%20Klein" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1</sup> and </span><span class="inlineblock "><div class='profile-card-drop' data-dropdown='profile-card-drop5596' data-options='is_hover:true, hover_timeout:5000'> Rolf W. Hartmann</div><div id="profile-card-drop5596" data-dropdown-content class="f-dropdown content profile-card-content" aria-hidden="true" tabindex="-1"><div class="profile-card__title"><div class="sciprofiles-link" style="display: inline-block"><div class="sciprofiles-link__link"><img class="sciprofiles-link__image" src="/bundles/mdpisciprofileslink/img/unknown-user.png" style="width: auto; height: 16px; border-radius: 50%;"><span class="sciprofiles-link__name">Rolf W. Hartmann</span></div></div></div><div class="profile-card__buttons" style="margin-bottom: 10px;"><a href="https://sciprofiles.com/profile/45913?utm_source=mdpi.com&utm_medium=website&utm_campaign=avatar_name" class="button button--color-inversed" target="_blank"> SciProfiles </a><a href="https://scilit.net/scholars?q=Rolf%20W.%20Hartmann" class="button button--color-inversed" target="_blank"> Scilit </a><a href="https://www.preprints.org/search?search1=Rolf%20W.%20Hartmann&field1=authors" class="button button--color-inversed" target="_blank"> Preprints.org </a><a href="https://scholar.google.com/scholar?q=Rolf%20W.%20Hartmann" class="button button--color-inversed" target="_blank" rels="noopener noreferrer"> Google Scholar </a></div></div><sup> 1,*</sup><span style="display: inline; margin-left: 5px;"></span><a class="toEncode emailCaptcha visibility-hidden" data-author-id="5596" href="/cdn-cgi/l/email-protection#91bef2fff5bcf2f6f8befdbef4fcf0f8fdbce1e3fee5f4f2e5f8feffb2a1a1a1a4a6a3a0f0a2a3a0f7a1f0a4f2a1a6a0f2a0f3a4f7a1a0a0a2a0a2a1a1a0f4a0a2a0f2a0a7a4f2a0a7a0a6"><sup><i class="fa fa-envelope-o"></i></sup></a></span> </div> <div class="nrm"></div> <span style="display:block; height:6px;"></span> <div></div> <div style="margin: 5px 0 15px 0;" class="hypothesis_container"> <div class="art-affiliations"> <div class="affiliation "> <div class="affiliation-item"><sup>1</sup></div> <div class="affiliation-name ">Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany</div> </div> <div class="affiliation "> <div class="affiliation-item"><sup>2</sup></div> <div class="affiliation-name ">Department of Molecular Virology, University of Heidelberg, Im Neuenheimer Feld 345, D-69120 Heidelberg, Germany</div> </div> <div class="affiliation "> <div class="affiliation-item"><sup>3</sup></div> <div class="affiliation-name ">Endotherm GmbH, Science-Park II, D-66123 Saarbrücken, Germany</div> </div> <div class="affiliation"> <div class="affiliation-item"><sup>*</sup></div> <div class="affiliation-name ">Author to whom correspondence should be addressed. </div> </div> </div> </div> <div class="bib-identity" style="margin-bottom: 10px;"> <em>Molecules</em> <b>2008</b>, <em>13</em>(5), 1081-1110; <a href="https://doi.org/10.3390/molecules13051081">https://doi.org/10.3390/molecules13051081</a> </div> <div class="pubhistory" style="font-weight: bold; padding-bottom: 10px;"> <span style="display: inline-block">Submission received: 26 March 2008</span> / <span style="display: inline-block">Revised: 2 May 2008</span> / <span style="display: inline-block">Accepted: 7 May 2008</span> / <span style="display: inline-block">Published: 7 May 2008</span> </div> <div class="highlight-box1"> <div class="download"> <a class="button button--color-inversed button--drop-down" data-dropdown="drop-download-1408" aria-controls="drop-supplementary-1408" aria-expanded="false"> Download <i class="material-icons">keyboard_arrow_down</i> </a> <div id="drop-download-1408" class="f-dropdown label__btn__dropdown label__btn__dropdown--button" data-dropdown-content aria-hidden="true" tabindex="-1"> <a class="UD_ArticlePDF" href="/1420-3049/13/5/1081/pdf?version=1403112490" data-name="Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization" data-journal="molecules">Download PDF</a> <br/> <a id="js-pdf-with-cover-access-captcha" href="#" data-target="/1420-3049/13/5/1081/pdf-with-cover" class="accessCaptcha">Download PDF with Cover</a> <br/> <a id="js-xml-access-captcha" href="#" data-target="/1420-3049/13/5/1081/xml" class="accessCaptcha">Download XML</a> <br/> <a href="/1420-3049/13/5/1081/epub" id="epub_link">Download Epub</a> <br/> </div> <div class="js-browse-figures" style="display: inline-block;"> <a href="#" class="button button--color-inversed margin-bottom-10 openpopupgallery UI_BrowseArticleFigures" data-target='article-popup' data-counterslink = "https://www.mdpi.com/1420-3049/13/5/1081/browse" >Browse Figures</a> </div> <div id="article-popup" class="popupgallery" style="display: inline; line-height: 200%"> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png?1553234365" title=" <strong>Figure 1</strong><br/> <p>Terfenadine.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png?1553234364" title=" <strong>Figure 2</strong><br/> <p>Reagents and conditions for the FC acylation and synthesized 1-aryl-ω-bromo ketones.</p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png?1553234365" title=" <strong>Figure 3</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png?1553234364" title=" <strong>Figure 4</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png?1553234365" title=" <strong>Figure 5</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png?1553234365" title=" <strong>Figure 6</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png?1553234365" title=" <strong>Figure 7</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png?1553234364" title=" <strong>Figure 8</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png?1553234365" title=" <strong>Figure 9</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png?1553234364" title=" <strong>Figure 10</strong><br/> <p></p> "> </a> <a href="https://pub.mdpi-res.com/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png?1553234365" title=" <strong>Figure 11</strong><br/> <p></p> "> </a> </div> <a class="button button--color-inversed" href="/1420-3049/13/5/1081/notes">Versions Notes</a> </div> </div> <div class="responsive-moving-container small hidden" data-id="article-counters" style="margin-top: 15px;"></div> <div class="html-dynamic"> <section> <div class="art-abstract art-abstract-new in-tab hypothesis_container"> <p> <div><section class="html-abstract" id="html-abstract"> <h2 id="html-abstract-title">Abstract</h2><b>:</b> <div class="html-p">Terfenadine (4-[4-(hydroxydiphenylmethyl)-1-piperidyl]-1-(4-<span class="html-italic">tert</span>-butyl-phenyl)-butan-1-ol) was identified in a biological screening to be a moderate inhibitor (27 % inhibition) of the CD81-LEL–HCV-E2 interaction. To increase the observed biological activity, 63 terfenadine derivates were synthesized via microwave assisted nucleophilic substitution. The prepared compounds were tested for their inhibitory potency by means of a fluorescence labeled antibody assay using HUH7.5 cells. Distinct structure-activity relationships could be derived. Optimization was successful, leading to <b>3g</b>, identfied as the most potent compound (69 % inhibition). Experiments with viral particles revealed that there might be additional HCV infection reducing mechanisms.</div> </section> <div id="html-keywords"> <div class="html-gwd-group"><div id="html-keywords-title">Keywords: </div><a href="/search?q=Hepatitis+C+Virus">Hepatitis C Virus</a>; <a href="/search?q=CD81-receptor">CD81-receptor</a>; <a href="/search?q=large+extracellular+loop">large extracellular loop</a>; <a href="/search?q=terfenadine+derivatives">terfenadine derivatives</a>; <a href="/search?q=microwave+assisted+syntheses">microwave assisted syntheses</a></div> </div> </div> </p> </div> </section> </div> <div class="hypothesis_container"> <ul class="menu html-nav" data-prev-node="#html-quick-links-title"> </ul> <div class="html-body"> <section id='Introduction' type='intro'><h2 data-nested='1'> Introduction</h2><div class='html-p'>Despite the discovery of the Hepatitis C Virus (HCV) more than 15 years ago, chronic HCV infection is still incurable in many patients, leading to cirrhosis, end-stage liver disease and hepatocellular carcinoma [<a href="#B1-molecules-13-01081" class="html-bibr">1</a>]. According to the 2002 WHO report, in 2001 more than 280,000 deaths worldwide were attributable to HCV infection [<a href="#B2-molecules-13-01081" class="html-bibr">2</a>]. The <span class='html-italic'>large extracellular loop</span> (LEL) of the human CD81 cell surface protein, a member of the tetraspanin family, was identified as a binding partner for the Hepatitis C Virus envelope glycoprotein E2 (HCV-E2) [<a href="#B3-molecules-13-01081" class="html-bibr">3</a>]. Since inhibition of this interaction prevents HCV from infecting hepatocytes, the HCV principal target cells [<a href="#B3-molecules-13-01081" class="html-bibr">3</a>], the aim of the present work was to prepare compounds which restrain the CD81-LEL–HCV-E2 interaction by binding to the LEL. Another approach to inhibit this interaction using compounds that bind to the E2 glycoprotein of HCV was recently published by Van Compernolle <span class='html-italic'>et al</span>. [<a href="#B3-molecules-13-01081" class="html-bibr">3</a>]. </div></section><section id='ResultsandDiscussion' type='results'><h2 data-nested='1'> Results and Discussion</h2><section id='BiologicalScreening' type=''><h4 class=html-italic data-nested='2'> Biological Screening</h4><div class='html-p'>The starting point of this work was a biological screening of natural products, current drugs and our in-house substance library (approximately 350 compounds, including several structurally different antihistamines) using a medium throughput assay developed in our group [<a href="#B4-molecules-13-01081" class="html-bibr">4</a>]. This assay is based on a procedure developed by Pileri <span class='html-italic'>et al</span>. [<a href="#B5-molecules-13-01081" class="html-bibr">5</a>], in which the compounds inhibit the binding of the fluorescence-labeled CD81 antibody JS81 to HUH7.5 cells.</div><div class='html-p'>As an outcome of this screening an antihistamine,, terfenadine (<a href="#molecules-13-01081-f001" class="html-fig">Figure 1</a>), was found to be a moderate inhibitor of the CD81-LEL–HCV-E2 interaction (27 % at 50 µM), whereas all other antihistamines showed no biological activity.</div><div class="html-fig-wrap" id="molecules-13-01081-f001"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f001"> <img alt="Molecules 13 01081 g001 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f001"></a> </div> </div> <div class="html-fig_description"> <b>Figure 1.</b> Terfenadine.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f001" > <div class="html-caption" > <b>Figure 1.</b> Terfenadine.</div> <div class="html-img"><img alt="Molecules 13 01081 g001" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g001.png" /></div> </div></section><section id='StructureModification' type=''><h4 class=html-italic data-nested='2'> Structure Modification</h4><div class='html-p'>Based on these results, a series of terfenadine derivatives was prepared seeking to increase the inhibitory activity and to derive structure-activity relationships. The following structural features were modified: length of the alkyl “linker” between the piperidine and the phenyl moiety, alkyl substituent on the phenyl ring, secondary hydroxy group and the azacyclonol moiety.</div></section><section id='Syntheses' type=''><h4 class=html-italic data-nested='2'> Syntheses</h4><div class='html-p'>The first step of the preparation was a Friedel-Crafts (FC) acylation of the benzene derivative with aluminium chloride as catalyst and the carboxylic acid chloride of the corresponding ω-bromo-carboxylic acid, prepared using thionyl chloride (<a href="#molecules-13-01081-f002" class="html-scheme">Scheme 1</a>). The synthesized 1-aryl-ω-bromo ketones are shown in <a href="#molecules-13-01081-t001" class="html-table">Table 1</a>.</div><div class="html-fig-wrap" id="molecules-13-01081-f002"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f002"> <img alt="Molecules 13 01081 g002 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f002"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 1.</b> Reagents and conditions for the FC acylation and synthesized 1-aryl-ω-bromo ketones.  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f002" > <div class="html-caption" > <b>Scheme 1.</b> Reagents and conditions for the FC acylation and synthesized 1-aryl-ω-bromo ketones. </div> <div class="html-img"><img alt="Molecules 13 01081 g002" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g002.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) 1. SOCl<sub>2</sub>, rt, 30 min 2. dry CH<sub>2</sub>Cl<sub>2</sub>, AlCl<sub>3</sub>, 0 °C, 45 min (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>).</div> </div><div class="html-table-wrap" id="molecules-13-01081-t001"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t001'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t001"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 1.</b> Synthesized 1-aryl-ω-bromo ketones <b>1a-1x</b> (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t001" > <table rules='all' style='border:solid thin'> <caption ><b>Table 1.</b> Synthesized 1-aryl-ω-bromo ketones <b>1a-1x</b> (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='7' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i001 > <img alt="Molecules 13 01081 i001" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i001.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1a</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1i</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1q</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1b</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1j</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1r</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Ethyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1c</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1k</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1s</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1d</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1l</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1t</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1e</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1m</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1u</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1f</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1n</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1v</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1g</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1o</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1w</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>tert</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>1h</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>1p</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>1x</b></td></tr></tbody> </table> </div><div class='html-p'>In the second reaction step (<a href="#molecules-13-01081-f003" class="html-scheme">Scheme 2</a>) the precursors <b>1a-1x</b> were coupled to azacyclonol according to a described procedure [<a href="#B6-molecules-13-01081" class="html-bibr">6</a>]. The classical nucleophilic substitution was optimized for microwave assisted synthesis. The desired compounds were obtained in satisfying yields in a very short time (5-45 minutes). This led to compounds <b>2a-2x</b>, shown in <a href="#molecules-13-01081-t002" class="html-table">Table 2</a>.</div><div class="html-fig-wrap" id="molecules-13-01081-f003"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f003"> <img alt="Molecules 13 01081 g003 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f003"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 2.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f003" > <div class="html-caption" > <b>Scheme 2.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g003" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g003.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, microwave: 150 Watt, 6.5 bar, 175 °C, 45 min (100 Watt, 140 °C, 3 h: <b>2g</b>, <b>2h</b>, <b>2t</b>, <b>2u</b>, <b>2v</b>, <b>2w</b>), n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>.</div> </div><div class="html-table-wrap" id="molecules-13-01081-t002"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t002'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t002"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 2.</b> Synthesized terfenadine derivatives <b>2a-2x</b> and <b>3a-3w</b> (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t002" > <table rules='all' style='border:solid thin'> <caption ><b>Table 2.</b> Synthesized terfenadine derivatives <b>2a-2x</b> and <b>3a-3w</b> (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='7' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i002 > <img alt="Molecules 13 01081 i002" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i002.png" /></span></td><td colspan='7' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i003 > <img alt="Molecules 13 01081 i003" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i003.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>n</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2a</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2i</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2q</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3a</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3i</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3q</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2b</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2j</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2r</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3b</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3j</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3r</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Ethyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2c</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2k</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2s</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3c</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3k</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3s</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2d</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2l</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2t</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3d</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3l</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3t</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2e</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2m</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2u</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3e</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3m</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3u</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2f</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2n</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2v</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3f</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3n</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3v</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2g</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2o</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2w</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3g</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3o</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>3w</b></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>tert</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>2h</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2p</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>2x</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3h</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3p</b></td><td align='center' valign='middle' class='html-align-center' >3</td><td align='center' valign='middle' class='html-align-center' ><b>terfenadine</b></td></tr></tbody> </table> </div><div class='html-p'>A sodium borohydride reduction (<a href="#molecules-13-01081-f004" class="html-scheme">Scheme 3</a>) of the ketone function followed. The prepared alcohols <b>3a-3w</b>, which were obtained as racemates, are also listed in <a href="#molecules-13-01081-t002" class="html-table">Table 2</a>.</div><div class="html-fig-wrap" id="molecules-13-01081-f004"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f004"> <img alt="Molecules 13 01081 g004 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f004"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 3.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f004" > <div class="html-caption" > <b>Scheme 3.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g004" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g004.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) NaBH<sub>4</sub>, MeOH, 0 °C, 1 h (n = 3-5; R = H; C<sub>1</sub>-C<sub>4</sub>).</div> </div><div class='html-p'>Since azacyclonol, the second component for the coupling reaction, was commercially available, this synthetic procedure facilitated the preparation of a large variety of compounds in a minimum amount of time. For further modification of the secondary hydroxy group the ester <b>5a</b>, the amide <b>5b</b> and the alkane <b>8a</b> were synthesized. </div><div class='html-p'>Activation of 6-bromo hexanoic acid with thionyl chloride followed by addition of commercially available 4-<span class='html-italic'>tert</span>-butyl phenol and 4-<span class='html-italic'>tert</span>-butyl aniline, respectively, led to the ω-bromo substituted precursors <b>4a</b> and <b>4b</b> (<a href="#molecules-13-01081-f005" class="html-scheme">Scheme 4</a>).</div><div class="html-fig-wrap" id="molecules-13-01081-f005"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f005"> <img alt="Molecules 13 01081 g005 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f005"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 4.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f005" > <div class="html-caption" > <b>Scheme 4.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g005" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g005.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) 1. SOCl<sub>2</sub>, rt, 1 h 2. NEt<sub>3</sub>, dry CH<sub>2</sub>Cl<sub>2</sub>, 0 °C 30 min, rt 1 h (X = -O-: <b>4a</b>, X = -NH-: <b>4b</b>).</div> </div><div class='html-p'>Next, these precursors were nucleophilically coupled to azacyclonol, leading to compounds 5a and 5b, respectively (<a href="#molecules-13-01081-f006" class="html-scheme">Scheme 5</a>).</div><div class="html-fig-wrap" id="molecules-13-01081-f006"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f006"> <img alt="Molecules 13 01081 g006 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f006"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 5.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f006" > <div class="html-caption" > <b>Scheme 5.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g006" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g006.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, 150 Watt, 140 °C, 1 h (X = -O-: <b>5a</b>, X = -NH-: <b>5b</b>).</div> </div><div class='html-p'>For the synthesis of <b>8a </b>compound <b>1h</b> was reduced using sodium borohydride. The resulting alcohol <b>6a</b> was converted into the corresponding alkane <b>7a </b> by means of a mixture of indium(III) chloride and chlorodiphenylsilane (<a href="#molecules-13-01081-f007" class="html-scheme">Scheme 6</a>) and subsequently coupled to azacyclonol, leading to compound <b>8a</b> (<a href="#molecules-13-01081-f008" class="html-scheme">Scheme 7</a>).</div><div class="html-fig-wrap" id="molecules-13-01081-f007"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f007"> <img alt="Molecules 13 01081 g007 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f007"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 6.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f007" > <div class="html-caption" > <b>Scheme 6.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g007" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g007.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) see <a href="#molecules-13-01081-f004" class="html-scheme">Scheme 3</a>; (ii) indium(III) chloride, chlorodiphenylsilane, dry dichloromethane, 3 h, rt.</div> </div><div class="html-fig-wrap" id="molecules-13-01081-f008"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f008"> <img alt="Molecules 13 01081 g008 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f008"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 7.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f008" > <div class="html-caption" > <b>Scheme 7.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g008" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g008.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, 50 Watt, 100 °C, 5 min</div> </div><div class='html-p'>The exchange of the azacyclonol component by smaller piperidine moieties started from the 1-aryl-ω-bromo ketone <b>1o </b> and was accomplished via microwave assisted nucleophilic substitution, followed by reduction of the ketone (<a href="#molecules-13-01081-f009" class="html-scheme">Scheme 8</a>). The prepared compounds <b>9a</b>-<b>9d</b>, as well as the corresponding alcohols <b>10a-10d</b>, obtained as racemates, are shown in <a href="#molecules-13-01081-t003" class="html-table">Table 3</a>.</div><div class="html-fig-wrap" id="molecules-13-01081-f009"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f009"> <img alt="Molecules 13 01081 g009 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f009"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 8.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f009" > <div class="html-caption" > <b>Scheme 8.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g009" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g009.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, microwave 150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH<sub>4</sub>, MeOH, 0 °C, 1 h (R = -H, -CH<sub>3</sub>, -OH, benzyl).</div> </div><div class="html-table-wrap" id="molecules-13-01081-t003"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t003'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t003"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 3.</b> Synthesized terfenadine derivatives <b>9a-9d</b> and <b>10a-10d</b>. </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t003" > <table rules='all' style='border:solid thin'> <caption ><b>Table 3.</b> Synthesized terfenadine derivatives <b>9a-9d</b> and <b>10a-10d</b>. <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='2' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i004 > <img alt="Molecules 13 01081 i004" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i004.png" /></span></td><td colspan='2' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i005 > <img alt="Molecules 13 01081 i005" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i005.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' ><b>9a</b></td><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' ><b>10a</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' ><b>9b</b></td><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' ><b>10b</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >Hydroxyl</td><td align='center' valign='middle' class='html-align-center' ><b>9c</b></td><td align='center' valign='middle' class='html-align-center' >Hydroxyl</td><td align='center' valign='middle' class='html-align-center' ><b>10c</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >Benzyl</td><td align='center' valign='middle' class='html-align-center' ><b>9d</b></td><td align='center' valign='middle' class='html-align-center' >Benzyl</td><td align='center' valign='middle' class='html-align-center' ><b>10d</b></td></tr></tbody> </table> </div><div class='html-p'>Furthermore, <b>1o</b> was reacted with morpholine and piperidin-4-one resulting in compounds <b>11a</b>, <b>12a</b> and <b>13a</b> (<a href="#molecules-13-01081-f010" class="html-scheme">scheme 9</a>). The morpholine derivative <b>12a</b> was obtained as a racemate. </div><div class="html-fig-wrap" id="molecules-13-01081-f010"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f010"> <img alt="Molecules 13 01081 g010 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f010"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 9.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f010" > <div class="html-caption" > <b>Scheme 9.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g010" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g010.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, microwave 150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH<sub>4</sub>, MeOH, 0 °C, 1 h.</div> </div><div class='html-p'>For the syntheses of the pyrrolidine compounds <b>15a</b> and <b>16a</b>, <b>1o</b> was coupled with diphenyl(pyrrolidin-3-yl)methanol (<b>14a</b>). The resulting ketone <b>15a</b> was reduced with sodium borohydride (<a href="#molecules-13-01081-f011" class="html-scheme">Scheme 10</a>), leading to the desired compound as a racemate.</div><div class="html-fig-wrap" id="molecules-13-01081-f011"> <div class='html-fig_img'> <div class="html-figpopup html-figpopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f011"> <img alt="Molecules 13 01081 g011 550" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011-550.jpg" /> <a class="html-expand html-figpopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#fig_body_display_molecules-13-01081-f011"></a> </div> </div> <div class="html-fig_description"> <b>Scheme 10.</b>  </div> </div> <div class="html-fig_show mfp-hide" id ="fig_body_display_molecules-13-01081-f011" > <div class="html-caption" > <b>Scheme 10.</b> </div> <div class="html-img"><img alt="Molecules 13 01081 g011" data-large="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png" data-original="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-g011.png" /></div> <div class='html-p'><span class='html-italic'>Reagents and conditions</span>: (i) K<sub>2</sub>CO<sub>3</sub>, catalytic KI and 18-crown-6, dry acetonitrile, microwave 150 Watt, 6.5 bar, 175 °C, 45 min; (ii) NaBH<sub>4</sub>, MeOH, 0 °C, 1 h.</div> </div></section><section id='Biologicalevaluation' type=''><h4 class=html-italic data-nested='2'> Biological evaluation</h4><div class='html-p'>The synthesized terfenadine derivatives were tested for their inhibitory potency using the antibody neutralization (AN) assay mentioned above (<a href="#molecules-13-01081-t004" class="html-table">Table 4</a>, <a href="#molecules-13-01081-t005" class="html-table">Table 5</a>, <a href="#molecules-13-01081-t006" class="html-table">Table 6</a>, <a href="#molecules-13-01081-t007" class="html-table">Table 7</a> and <a href="#molecules-13-01081-t008" class="html-table">Table 8</a>) [<a href="#B4-molecules-13-01081" class="html-bibr">4</a>]. In this assay the potential inhibitors and the fluorescence-labeled antibody JS81 compete for binding to the LEL on the CD81 receptor molecule. The reduction of the interaction of JS81 with CD81 on HUH7.5 cells caused by the compounds decreases fluorescence which is measured by FACS in comparison to untreated control cells.</div><div class='html-p'>The % inhibition values of compounds <b>2a-2x</b> (<a href="#molecules-13-01081-t004" class="html-table">Table 4</a>) and <b>3a-3w</b> (<a href="#molecules-13-01081-t005" class="html-table">Table 5</a>) show that the alkyl substituent R on the phenyl ring has a major influence on the activity. Another important feature is obviously the length of the linker, whereas the activities of the ketones (<a href="#molecules-13-01081-t004" class="html-table">Table 4</a>) and the corresponding alcohols (<a href="#molecules-13-01081-t005" class="html-table">Table 5</a>) do not differ significantly, at least in case of the <span class='html-italic'>n</span>-propyl and <span class='html-italic'>n</span>-butyl compounds. </div><div class="html-table-wrap" id="molecules-13-01081-t004"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t004'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t004"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 4.</b> Inhibition of protein interaction in AN assay by compounds <b>2a</b>-<b>2x </b>(concentration: 50 µM, standard deviation ≤ 6 %). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t004" > <table rules='all' style='border:solid thin'> <caption ><b>Table 4.</b> Inhibition of protein interaction in AN assay by compounds <b>2a</b>-<b>2x </b>(concentration: 50 µM, standard deviation ≤ 6 %). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='7' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i006 > <img alt="Molecules 13 01081 i006" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i006.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 5</b></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 4</b></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 3</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' ><b>2a</b></td><td align='center' valign='middle' class='html-align-center' >10</td><td align='center' valign='middle' class='html-align-center' ><b>2i</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>2q</b></td><td align='center' valign='middle' class='html-align-center' >7</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' ><b>2b</b></td><td align='center' valign='middle' class='html-align-center' >12</td><td align='center' valign='middle' class='html-align-center' ><b>2j</b></td><td align='center' valign='middle' class='html-align-center' >8</td><td align='center' valign='middle' class='html-align-center' ><b>2r</b></td><td align='center' valign='middle' class='html-align-center' >7</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Ethyl</td><td align='center' valign='middle' class='html-align-center' ><b>2c</b></td><td align='center' valign='middle' class='html-align-center' >42</td><td align='center' valign='middle' class='html-align-center' ><b>2k</b></td><td align='center' valign='middle' class='html-align-center' >24</td><td align='center' valign='middle' class='html-align-center' ><b>2s</b></td><td align='center' valign='middle' class='html-align-center' >1</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' ><b>2d</b></td><td align='center' valign='middle' class='html-align-center' >59</td><td align='center' valign='middle' class='html-align-center' ><b>2l</b></td><td align='center' valign='middle' class='html-align-center' >64</td><td align='center' valign='middle' class='html-align-center' ><b>2t</b></td><td align='center' valign='middle' class='html-align-center' >57</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' ><b>2e</b></td><td align='center' valign='middle' class='html-align-center' >63</td><td align='center' valign='middle' class='html-align-center' ><b>2m</b></td><td align='center' valign='middle' class='html-align-center' >29</td><td align='center' valign='middle' class='html-align-center' ><b>2u</b></td><td align='center' valign='middle' class='html-align-center' >41</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>2f</b></td><td align='center' valign='middle' class='html-align-center' >56</td><td align='center' valign='middle' class='html-align-center' ><b>2n</b></td><td align='center' valign='middle' class='html-align-center' >57</td><td align='center' valign='middle' class='html-align-center' ><b>2v</b></td><td align='center' valign='middle' class='html-align-center' >56</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>2g</b></td><td align='center' valign='middle' class='html-align-center' >46</td><td align='center' valign='middle' class='html-align-center' ><b>2o</b></td><td align='center' valign='middle' class='html-align-center' >60</td><td align='center' valign='middle' class='html-align-center' ><b>2w</b></td><td align='center' valign='middle' class='html-align-center' >44</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>tert</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>2h</b></td><td align='center' valign='middle' class='html-align-center' >49</td><td align='center' valign='middle' class='html-align-center' ><b>2p</b></td><td align='center' valign='middle' class='html-align-center' >53</td><td align='center' valign='middle' class='html-align-center' ><b>2x</b></td><td align='center' valign='middle' class='html-align-center' >37</td></tr></tbody> </table> </div><div class="html-table-wrap" id="molecules-13-01081-t005"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t005'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t005"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 5.</b> Inhibition of protein interaction in AN assay by compounds <b>3a-3w</b> (concentration: 50 µM, standard deviation ≤ 6 %). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t005" > <table rules='all' style='border:solid thin'> <caption ><b>Table 5.</b> Inhibition of protein interaction in AN assay by compounds <b>3a-3w</b> (concentration: 50 µM, standard deviation ≤ 6 %). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='7' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i007 > <img alt="Molecules 13 01081 i007" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i007.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 5</b></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 4</b></td><td colspan='2' align='center' valign='middle' class='html-align-center' ><b>n = 3</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >H</td><td align='center' valign='middle' class='html-align-center' ><b>3a</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3i</b></td><td align='center' valign='middle' class='html-align-center' >1</td><td align='center' valign='middle' class='html-align-center' ><b>3q</b></td><td align='center' valign='middle' class='html-align-center' >5</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Methyl</td><td align='center' valign='middle' class='html-align-center' ><b>3b</b></td><td align='center' valign='middle' class='html-align-center' >8</td><td align='center' valign='middle' class='html-align-center' ><b>3j</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>3r</b></td><td align='center' valign='middle' class='html-align-center' >4</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >Ethyl</td><td align='center' valign='middle' class='html-align-center' ><b>3c</b></td><td align='center' valign='middle' class='html-align-center' >13</td><td align='center' valign='middle' class='html-align-center' ><b>3k</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3s</b></td><td align='center' valign='middle' class='html-align-center' >4</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' ><b>3d</b></td><td align='center' valign='middle' class='html-align-center' >32</td><td align='center' valign='middle' class='html-align-center' ><b>3l</b></td><td align='center' valign='middle' class='html-align-center' >53</td><td align='center' valign='middle' class='html-align-center' ><b>3t</b></td><td align='center' valign='middle' class='html-align-center' >23</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Propyl</td><td align='center' valign='middle' class='html-align-center' ><b>3e</b></td><td align='center' valign='middle' class='html-align-center' >9</td><td align='center' valign='middle' class='html-align-center' ><b>3m</b></td><td align='center' valign='middle' class='html-align-center' >4</td><td align='center' valign='middle' class='html-align-center' ><b>3u</b></td><td align='center' valign='middle' class='html-align-center' >11</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>n</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>3f</b></td><td align='center' valign='middle' class='html-align-center' >49</td><td align='center' valign='middle' class='html-align-center' ><b>3n</b></td><td align='center' valign='middle' class='html-align-center' >49</td><td align='center' valign='middle' class='html-align-center' ><b>3v</b></td><td align='center' valign='middle' class='html-align-center' >64</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>iso</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>3g</b></td><td align='center' valign='middle' class='html-align-center' >69</td><td align='center' valign='middle' class='html-align-center' ><b>3o</b></td><td align='center' valign='middle' class='html-align-center' >67</td><td align='center' valign='middle' class='html-align-center' ><b>3w</b></td><td align='center' valign='middle' class='html-align-center' >42</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><span class='html-italic'>tert</span>-Butyl</td><td align='center' valign='middle' class='html-align-center' ><b>3h</b></td><td align='center' valign='middle' class='html-align-center' >58</td><td align='center' valign='middle' class='html-align-center' ><b>3p</b></td><td align='center' valign='middle' class='html-align-center' >44</td><td align='center' valign='middle' class='html-align-center' ><b>terfenadine</b></td><td align='center' valign='middle' class='html-align-center' >27</td></tr></tbody> </table> </div><div class='html-p'>Increasing the size of R from hydrogen to bulkier alkyl substituents increases inhibition. A maximum inhibition, not depending on the linker length, could be reached by the use of <span class='html-italic'>n</span>-propyl for the ketones and <span class='html-italic'>iso</span>-butyl for the alcohols, with the exception of compounds <b>2d</b> and <b>3w</b>, which are less active than the analogous <b>2e </b>and <b>3v</b>. Generally, compounds with n = 3 show a lower inhibition than those with n = 4 or 5, with the exception of <b>3v</b>, which is more active than <b>3f </b>and <b>3n</b>. Furthermore, reduction of the ketones <b>2a</b>-<b>2x </b> to the corresponding alcohols <b>3a</b>-<b>3w </b> and terfenadine led to a decreased activity for compounds with small substituents at the phenyl ring, whereas a reduction of bulky substituted compounds led to derivatives with comparable inhibition. The reduction of the ketones with R = <span class='html-italic'>iso</span>-propyl to the corresponding alcohols led to a nearly complete loss of biological activity. The most active compound in this series of terfenadine derivatives is <b>3g </b>(69 % inhibition). Therefore, the hexanol linker combined with an <span class='html-italic'>iso</span>-butyl group at the phenyl ring is the most favorable substitution pattern in this class of compounds.</div><div class='html-p'>Replacement of the azacyclonol moiety by smaller piperidine residues (<b>9a</b>-<b>9c</b>, <b>10a</b>-<b>10c</b> and <b>11a</b>-<b>13a</b>) led to a loss of inhibitory activity compared to the reference compounds <b>2o</b> and <b>3o </b>(<a href="#molecules-13-01081-t006" class="html-table">Table 6</a>). Substitution of the piperidine group by a 4-benzyl group (<b>9d</b> and <b>10d</b>) increased the inhibition to a moderate level. Again bulky substituents are essential for activity at this part of the molecule.</div><div class="html-table-wrap" id="molecules-13-01081-t006"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t006'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t006"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 6.</b> Inhibition of protein interaction in AN assay by compounds <b>9a-13a</b> compared to compounds <b>2o</b> and <b>3o</b> (concentration: 50 µM, standard deviation ≤ 6 %). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t006" > <table rules='all' style='border:solid thin'> <caption ><b>Table 6.</b> Inhibition of protein interaction in AN assay by compounds <b>9a-13a</b> compared to compounds <b>2o</b> and <b>3o</b> (concentration: 50 µM, standard deviation ≤ 6 %). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='3' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i008 > <img alt="Molecules 13 01081 i008" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i008.png" /></span></td><td colspan='2' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i009 > <img alt="Molecules 13 01081 i009" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i009.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>R</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >azacyclonol</td><td align='center' valign='middle' class='html-align-center' ><b>2o</b></td><td align='center' valign='middle' class='html-align-center' >60</td><td align='center' valign='middle' class='html-align-center' ><b>3o</b></td><td align='center' valign='middle' class='html-align-center' >67</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i010 > <img alt="Molecules 13 01081 i010" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i010.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>9a</b></td><td align='center' valign='middle' class='html-align-center' >7</td><td align='center' valign='middle' class='html-align-center' ><b>10a</b></td><td align='center' valign='middle' class='html-align-center' >5</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i011 > <img alt="Molecules 13 01081 i011" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i011.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>9b</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' ><b>10b</b></td><td align='center' valign='middle' class='html-align-center' >7</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i012 > <img alt="Molecules 13 01081 i012" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i012.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>9c</b></td><td align='center' valign='middle' class='html-align-center' >7</td><td align='center' valign='middle' class='html-align-center' ><b>10c</b></td><td align='center' valign='middle' class='html-align-center' >6</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i013 > <img alt="Molecules 13 01081 i013" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i013.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>9d</b></td><td align='center' valign='middle' class='html-align-center' >29</td><td align='center' valign='middle' class='html-align-center' ><b>10d</b></td><td align='center' valign='middle' class='html-align-center' >31</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i014 > <img alt="Molecules 13 01081 i014" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i014.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>11a</b></td><td align='center' valign='middle' class='html-align-center' >8</td><td align='center' valign='middle' class='html-align-center' ><b>12a</b></td><td align='center' valign='middle' class='html-align-center' >4</td></tr><tr ><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i015 > <img alt="Molecules 13 01081 i015" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i015.png" /></span></td><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' ><b>13a</b></td><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' >5</td><td style='border-right:hidden; border-bottom:hidden' align='center' valign='middle' class='html-align-center' > </td><td style='border-left:hidden; border-right:hidden; border-bottom:hidden' align='center' valign='middle' class='html-align-center' > </td></tr></tbody> </table> </div><div class='html-p'>Reduction of the secondary hydroxy group of <b>3h</b> to the corresponding alkane <b>8a</b> led to a strong decrease of inhibition (<a href="#molecules-13-01081-t007" class="html-table">Table 7</a>). Exchange of the ketone of <b>2h</b> by an ester function (compound <b>5a</b>) did not influence the inhibitory activity, whereas an amide group (compound <b>5b</b>) increased the inhibition. These SAR results indicate that the functional group X might act as an H-bond acceptor interacting with the CD81 protein.</div><div class="html-table-wrap" id="molecules-13-01081-t007"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t007'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t007"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 7.</b> Inhibition of protein interaction in AN assay by compounds <b>5a</b>-<b>5b</b>, <b>8a</b> compared to compounds <b>2h</b> and <b>3h </b>(R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t007" > <table rules='all' style='border:solid thin'> <caption ><b>Table 7.</b> Inhibition of protein interaction in AN assay by compounds <b>5a</b>-<b>5b</b>, <b>8a</b> compared to compounds <b>2h</b> and <b>3h </b>(R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='6' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i016 > <img alt="Molecules 13 01081 i016" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i016.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>X</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>X</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i017 > <img alt="Molecules 13 01081 i017" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i017.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>3h</b></td><td align='center' valign='middle' class='html-align-center' >58</td><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i018 > <img alt="Molecules 13 01081 i018" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i018.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>8a</b></td><td align='center' valign='middle' class='html-align-center' >9</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i019 > <img alt="Molecules 13 01081 i019" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i019.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>2h</b></td><td align='center' valign='middle' class='html-align-center' >49</td><td align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i020 > <img alt="Molecules 13 01081 i020" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i020.png" /></span></td><td align='center' valign='middle' class='html-align-center' ><b>5a</b></td><td align='center' valign='middle' class='html-align-center' >48</td></tr><tr ><td style='border-left:hidden; border-bottom:hidden; border-right:hidden' align='center' valign='middle' class='html-align-center' > </td><td style='border-left:hidden; border-bottom:hidden; border-right:hidden' align='center' valign='middle' class='html-align-center' > </td><td style='border-left:hidden; border-bottom:hidden' align='center' valign='middle' class='html-align-center' > </td><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i021 > <img alt="Molecules 13 01081 i021" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i021.png" /></span></td><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' ><b>5b</b></td><td style='border-top:hidden' align='center' valign='middle' class='html-align-center' >57</td></tr></tbody> </table> </div><div class='html-p'>Exchange of the piperidine of the azacyclonol moiety of <b>2o</b> and <b>3o</b> by pyrrolidine (compounds <b>15a</b> and <b>16a</b>) did not lead to a significant change of the inhibitory activity (<a href="#molecules-13-01081-t008" class="html-table">Table 8</a>). Obviously due to the flexibility of the chain, appropriate conformations can be found for both heterocycles.</div><div class="html-table-wrap" id="molecules-13-01081-t008"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t008'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t008"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 8.</b> Inhibition of protein interaction in AN assay by compounds 15a, 16a compared to compounds 2p and 3p (R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %). </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t008" > <table rules='all' style='border:solid thin'> <caption ><b>Table 8.</b> Inhibition of protein interaction in AN assay by compounds 15a, 16a compared to compounds 2p and 3p (R = azacyclonol, concentration: 50 µM, standard deviation ≤ 6 %). <div class='html-caption-img'></div></caption> <tbody ><tr ><td colspan='3' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i022 > <img alt="Molecules 13 01081 i022" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i022.png" /></span></td><td colspan='2' align='center' valign='middle' class='html-align-center' > <span class='html-fig-inline' id = molecules-13-01081-i023 > <img alt="Molecules 13 01081 i023" data-lsrc="/molecules/molecules-13-01081/article_deploy/html/images/molecules-13-01081-i023.png" /></span></td></tr><tr ><td align='center' valign='middle' class='html-align-center' ><b>X</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td><td align='center' valign='middle' class='html-align-center' ><b>compound</b></td><td align='center' valign='middle' class='html-align-center' ><b>inhibition (%)</b></td></tr><tr ><td align='center' valign='middle' class='html-align-center' >O</td><td align='center' valign='middle' class='html-align-center' ><b>2o</b></td><td align='center' valign='middle' class='html-align-center' >60</td><td align='center' valign='middle' class='html-align-center' ><b>15a</b></td><td align='center' valign='middle' class='html-align-center' >64</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' >OH</td><td align='center' valign='middle' class='html-align-center' ><b>3o</b></td><td align='center' valign='middle' class='html-align-center' >67</td><td align='center' valign='middle' class='html-align-center' ><b>16a</b></td><td align='center' valign='middle' class='html-align-center' >62</td></tr></tbody> </table> </div><div class='html-p'>Selected compounds with high, moderate and low inhibition in the AN assay were tested for their inhibition in an infectivity assay developed by Pietschmann and coworkers [<a href="#B7-molecules-13-01081" class="html-bibr">7</a>] (<a href="#molecules-13-01081-t009" class="html-table">Table 9</a>), in which HUH7.5 cells were incubated with HCV particles of the LUC-Jc1 genome (genotype 2a) [<a href="#B8-molecules-13-01081" class="html-bibr">8</a>] and potential inhibitors. After 48 hours, the cells were lysed and luciferase activity (a marker of infection and viral replication) was measured. The infectivity assay was performed at the highest non-cytotoxic concentrations of the compounds (0.5 µM: <b>2e</b>, <b>2s</b>, <b>3f</b>, <b>3g</b>, <b>3i</b>, <b>8a</b> and 5 µM: <b>3q</b>, <b>10d</b>).</div><div class='html-p'>Compounds with high biological activity in the neutralization assay showed good inhibition in the infectivity assay as well. This clearly indicates that inhibition of the protein-protein interaction leads to a reduction of infectivity. On the other hand there are compounds which reduced infectivity without having been active in the AN assay. One plausible reason for this phenomenon could be an interaction of these compounds with an additional target which is involved in viral infection. </div><div class="html-table-wrap" id="molecules-13-01081-t009"> <div class="html-table_wrap_td" > <div class="html-tablepopup html-tablepopup-link" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href='#table_body_display_molecules-13-01081-t009'> <img alt="Table" data-lsrc="https://www.mdpi.com/img/table.png" /> <a class="html-expand html-tablepopup" data-counterslinkmanual = "https://www.mdpi.com/1420-3049/13/5/1081/display" href="#table_body_display_molecules-13-01081-t009"></a> </div> </div> <div class="html-table_wrap_discription"> <b>Table 9.</b> Inhibition of infectivity of viral particles by selected compounds. </div> </div> <div class="html-table_show mfp-hide " id ="table_body_display_molecules-13-01081-t009" > <table rules='all' style='border:solid thin'> <caption ><b>Table 9.</b> Inhibition of infectivity of viral particles by selected compounds. <div class='html-caption-img'></div></caption> <thead ><tr ><th align='center' valign='middle' class='html-align-center' >Compound</th><th align='center' valign='middle' class='html-align-center' ><b>Antibody neutralization assay (inhibition (%), 50 µM)</b></th><th align='center' valign='middle' class='html-align-center' >Infectivity assay with viral particles <b>(inhibition (%), 0.5 µM)</b></th></tr></thead><tbody ><tr ><td align='center' valign='middle' class='html-align-center' ><b>2e</b></td><td align='center' valign='middle' class='html-align-center' >63</td><td align='center' valign='middle' class='html-align-center' >43</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>2s</b></td><td align='center' valign='middle' class='html-align-center' >1</td><td align='center' valign='middle' class='html-align-center' >19</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>3f</b></td><td align='center' valign='middle' class='html-align-center' >49</td><td align='center' valign='middle' class='html-align-center' >40</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>3g</b></td><td align='center' valign='middle' class='html-align-center' >69</td><td align='center' valign='middle' class='html-align-center' >32</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>3i</b></td><td align='center' valign='middle' class='html-align-center' >1</td><td align='center' valign='middle' class='html-align-center' >27</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>3q</b></td><td align='center' valign='middle' class='html-align-center' >5</td><td align='center' valign='middle' class='html-align-center' >33<sup>a</sup></td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>8a</b></td><td align='center' valign='middle' class='html-align-center' >9</td><td align='center' valign='middle' class='html-align-center' >27</td></tr><tr style='border-top:hidden' ><td align='center' valign='middle' class='html-align-center' ><b>10d</b></td><td align='center' valign='middle' class='html-align-center' >31</td><td align='center' valign='middle' class='html-align-center' >45<sup>a</sup></td></tr></tbody> </table> <div class='html-table_foot html-p'><div class='html-p' style='text-indent:0em;'><span class='html-fn-content'>Concentration: 0.5 µM, <sup>a </sup>5 µM, standard deviation ≤ 14 % compared to AN assay data.</span></div></div> </div></section></section><section id='Conclusions' type='conclusions'><h2 data-nested='1'> Conclusions</h2><div class='html-p'>After having identified terfenadine as an active compound inhibiting the CD81-LEL–HCV-E2 interaction by 27 %, the compound was structurally modified with the aim of increasing the activity. The results obtained clearly demonstrate that a bulky substituent at the phenyl moiety as well as an additional bulky substituent at the other part of the molecule (like azacyclonol) are necessary for activity as well as the secondary OH-group. Another H-bond acceptor like ketone, ester or amide can replace the latter. Importantly, the activity of the parent compound can be increased by elongation of the alkyl chain resulting in <b>3g</b> with an inhibition of 69 %. A further experiment with viral particles and HUH7.5 cells showed that there are possibly further mechanisms by which the test compounds unfold their anti-viral activity. These mechanisms remain to be elucidated.</div></section><section id='Experimental' type='methods'><h2 data-nested='1'> Experimental</h2><section id='General' type=''><h4 class=html-italic data-nested='2'> General</h4><div class='html-p'>Solvents and reagents were used as received from commercial distributors without further purification. Anhydrous reactions were conducted under a nitrogen atmosphere. Proton and carbon NMR spectra (in CDCl<sub>3</sub>, unless otherwise noted) were recorded on a Bruker AM 500 instrument The proton NMR spectra were recorded at 500 MHz, the carbon NMR spectra at 125 MHz. Chemical shifts δ are reported in ppm units. Molecular mass was determined by liquid chromatography – tandem mass spectrometry (LC-MS/MS) using a TSQ Quantum from Thermo Finnigan equipped with an electro spray interface and connected to a Surveyor HPLC (Thermo Finnigan). Positive and negative ion mass spectra were recorded (mass range m/z 150–1500) in normal scan mode. Melting points were determined using a Stuart Scientific SMP3 melting point apparatus. IR measurements were performed on a Bruker Vector 33 at a frequency range from 4000–250 cm<sup>-1</sup>. Wave numbers υ are reported in cm<sup>-1</sup>. Microwave assisted syntheses was performed using a CEM DISCOVER microwave oven or a MLS MultiSYNTH microwave oven respectively. Preparative HPLC was carried out using an Agilent Technologies, 1200 Series Isocratic, with an Agilent Prep-C18 (5 µm; 30x100mm) preparative column using 70:30 methanol/water as eluent. Flash chromatography was performed using Merck silica gel 35/40–63/70.</div></section><section id='Antibodyneutralizationassay' type=''><h4 class=html-italic data-nested='2'> Antibody neutralization assay.</h4><div class='html-p'>For the antibody neutralization assay HUH7.5 cells were used, derived from a human hepatoma cell line which was preselected via FACS for cells displaying high amounts of CD81 on their cell surface. Cells were grown under standard conditions (Dulbecco’s Modified Eagle’s Medium with 10 % FCS, 1% penicillin/streptavidin, pH 7.4, at 37°C with 5% CO<sub>2</sub>). 1∙10<sup>5</sup> cells were incubated with 100 µL (50µM) of the potential inhibitor. The inhibitor solution contained 1 % DMSO, a concentration tolerated by the used HUH7.5 cells and without influence on MFI (mean fluorescence intensity) values (data not shown). Incubation was performed in 96 transwell plates for 10 minutes at room temperature. Subsequently 4 µL of the fluorescence-labeled anti human CD81 antibody JS81 (Pharmingen) and 21 µL of phosphate buffered saline buffer (PBS) were added and kept at room temperature for 10 minutes. The final concentration of JS81 in the assay was 1.6∙10<sup>-3</sup> µg/µL. After addition of 125 µL of PBS the cell suspension was incubated in the dark for 5 hours followed by FACS (Becton Dickison – FACS Calibur; software: Cell Quest Pro) analysis. Ten thousand vital cells out of a predetermined area were analyzed for their MFI.</div></section><section id='Infectivityassay' type=''><h4 class=html-italic data-nested='2'> Infectivity assay.</h4><div class='html-p'><span class='html-italic'>In vitro</span> synthesis of the LUC-Jc1 RNA genome in which the luciferase reporter gene was inserted into the genome of the Jc1 HCV variant and electroporation of Huh-7 cells was performed as described previously [<a href="#B9-molecules-13-01081" class="html-bibr">9</a>, <a href="#B10-molecules-13-01081" class="html-bibr">10</a>]. We collected culture medium containing viral particles 48 h after transfection. HUH7.5 target cells were seeded 24 h before infection at a density of 6∙10<sup>5</sup> cells/well in a 24 well plate. Cells were infected with 200 µL inoculum containing the potential inhibitors at 5 µM or 0.5 µM for 4 h. Concentrations were chosen according to the highest non-cytotoxic concentration of the given compound. Cells were washed, complete medium was added and cells were cultured for 48 h. Afterwards cells were lysed for luciferase assay as previously described [<a href="#B7-molecules-13-01081" class="html-bibr">7</a>]. </div></section><section id='Chemistry' type=''><h4 class=html-italic data-nested='2'> Chemistry</h4><section id='' type=''><h4 class= data-nested='3'> <span class='html-italic'>General procedure for</span> <span class='html-italic'>the Friedel-Crafts-acylation</span></h4><div class='html-p'>The carboxylic acid was stirred with thionyl chloride (10 mL) at room temperature for 1h. After removing the excess of thionyl chloride under reduced pressure, dry dichloromethane (15 mL) and the benzene derivative (1 equivalent, referring to the carboxylic acid) were added. The solution was cooled to 0 °C and AlCl<sub>3</sub> (1.2 equivalents) were added. After stirring at that temperature for 45 min, the mixture was hydrolyzed, the layers separated and the water phase was extracted with dichloromethane two times. The combined organic layers were dried and the solvent removed. Flash chromatography using 1/15 ethyl acetate/n-hexane as eluent led to the desired compounds.</div></section><section id='' type=''><h4 class= data-nested='3'> <span class='html-italic'>General procedure for the</span> <span class='html-italic'>nucleophilic substitution</span></h4><div class='html-p'>Azacyclonol (1 equivalent), ketone (1 equivalent), potassium carbonate (5 equivalents), a catalytic amount of potassium iodide and 18-crown-6 were stirred in dry acetonitrile (4 mL) in the microwave (CEM Discover) at 150 Watt, 6.5 bar, 175 °C for 45 min or (MultiSYNTH) at 100 Watt, 140 °C, 3 h <b>(2g, 2h, 2t, 2u, 2v, 2w)</b> or at 50 Watt, 100 °C, 5 min (<b>8a</b>). The microwave assisted reactions were performed in a continuous air stream cooled closed vessel. Reaction temperature was monitored via an IR sensor in both microwave ovens and an additional fiber optic component in case of the MultiSYNTH. After filtering off the remaining precipitate the solvent was removed. The impurities could not be removed completely by flash chromatography (6/1 ethyl acetate/n-hexane + 3 % NEt<sub>3</sub>), so preparative HPLC (isocratic 70/30 MeOH/H<sub>2</sub>O) was performed and the pure product isolated.</div></section><section id='' type=''><h4 class= data-nested='3'> <span class='html-italic'>General procedure for the reduction of</span> <span class='html-italic'>the ketones</span></h4><div class='html-p'>Sodium borohydride (5 equivalents) and ketone (1 equivalent) were added to 2 mL methanol at 0 °C. After stirring for 30 min a spatula tip of sodium borohydride was added to the mixture which was stirred for another 30 min at 0 °C. The mixture was hydrolyzed using 2 mL NH<sub>4</sub>Cl-solution. After removing the solvents under reduced pressure, the remaining solid was washed two times with methanol and ethyl acetate (2 mL each). The combined organic layers were freed from solvent and the raw product was purified by preparative HPLC (isocratic MeOH/H<sub>2</sub>O: 70/30) to give the racemates in satisfying yields.</div></section><section id='' type=''><h4 class= data-nested='3'> <span class='html-italic'>General procedure for the ester and amide</span> <span class='html-italic'>coupling</span></h4><div class='html-p'>The carboxylic acid (1 equivalent) was stirred with an excess of thionyl chloride for 1 hour at room temperature. The resulting clear solution was freed from remaining thionyl chloride under reduced pressure. The acid chloride was dissolved in dry dichloromethane and added dropwise at 0 °C to a solution of the corresponding alcohol or amine (1.2 equivalents) and an equimolar amount of triethylamine in dry dichloromethane. After stirring for 30 minutes at 0 °C the mixture was warmed to room temperature and stirred for 1 hour. The precipitated solid was filtered off. The solvent was removed and the raw product purified by column flash chromatography using an ethyl acetate/n-hexane mixture.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-phenylhexan-1-one</span> (<b>1a</b>). Yield: 26 %; <sup>1</sup>H-NMR: 7.88–7.85 (2 H, m), 7.49–7.45 (1 H, m), 7.39–7.35 (2 H, m), 3.35–3.32 (2 H, m), 2.92–2.88 (2 H, m), 1.86–1.79 (2 H, m), 1.72–1.64 (2 H, m), 1.48–1.40 (2 H, m) [Lit. [<a href="#B11-molecules-13-01081" class="html-bibr">11</a>] 400 MHz, CDCl<sub>3</sub>: 7.94 (2 H, m), 7.55 (1 H, m), 7.45 (2 H, m), 3.41 (2 H, t, <span class='html-italic'>J</span> = 6.80), 2.98 (2 H, t, <span class='html-italic'>J</span> = 7.00), 1.90 (2 H, m), 1.76 (2 H, m), 1.53 (2 H, m)]; <sup>13</sup>C-NMR: 199.96, 136.95, 133.02, 128.61, 128.02, 38.29, 33.69, 32.66, 27.89, 23.33.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-methylphenyl)hexan-1-one</span> (<b>1b</b>). Yield: 50 %; <sup>1</sup>H-NMR: 7.76 (2 H, d, <span class='html-italic'>J</span> = 8.06), 7.16 (2 H, d, <span class='html-italic'>J</span> = 7.98), 3.34–3.31 (2 H, t, <span class='html-italic'>J</span> = 6.78), 2.88–2.84 (2 H, t, <span class='html-italic'>J</span> = 7.44), 2.31 (3 H, s), 1.85–1.78 (2 H, m), 1.70–1.62 (2 H, m), 1.47–1.39 (2 H, m) [Lit. [<a href="#B12-molecules-13-01081" class="html-bibr">12</a>] CDCl<sub>3</sub>: 7.85 (2 H, d, <span class='html-italic'>J</span> = 7.30), 7.25 (2 H, d, <span class='html-italic'>J</span> = 8.60), 3.42 (2 H, d, <span class='html-italic'>J</span> = 8.60), 2.96 (2 H, t, <span class='html-italic'>J</span> = 7.30), 2,41 (3 H, s), 1.97–1.86 (2 H, m), 1.82–1.74 (2 H, m), 1.58–1.47 (2 H, m)]; <sup>13</sup>C-NMR: 199.61, 143.72, 134.47, 129.26, 128.13, 38.14, 33.67, 32.65, 27.89, 23.41, 21.62.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-ethylphenyl)hexan-1-one</span> (<b>1c</b>). Yield: 75 %; <sup>1</sup>H-NMR: 7.89 (2 H, d, <span class='html-italic'>J</span> = 8.34), 7.29 (2 H, d, <span class='html-italic'>J</span> = 8.49), 3.43 (2 H, t, <span class='html-italic'>J</span> = 6.79), 2.99–2.96 (2 H, m), 2.74–2.68 (2 H, m), 1.95–1.88 (2 H, m), 1.81–1.73 (2 H, m), 1.57–1.50 (2 H, m), 1.26 (3 H, t, <span class='html-italic'>J</span> = 7.60) [Lit. [<a href="#B12-molecules-13-01081" class="html-bibr">12</a>] CDCl<sub>3</sub>: 7.88 (1 H, d, <span class='html-italic'>J</span> = 8.60), 7.28 (1 H, d, <span class='html-italic'>J</span> = 8.60), 3.43 (2 H, t, <span class='html-italic'>J</span> = 7.00), 2.97 (2 H, t, <span class='html-italic'>J</span> = 7.30), 2.71 (2 H, q, <span class='html-italic'>J</span> = 7.20), 2.04–1.48 (6 H, m), 1.26 (3 H, t, <span class='html-italic'>J</span> = 7.60)]; <sup>13</sup>C-NMR: 199.65, 148.91, 133.65, 127.22, 127.06, 37.16, 32.67, 31.64, 27.91, 26.89, 22.41, 14.22.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-n-propylphenyl)hexan-1-one</span> (<b>1d</b>). Yield: 74 %; <sup>1</sup>H-NMR: 7.84 (2 H, d, <span class='html-italic'>J</span> = 8.32), 7.23 (2 H, d, <span class='html-italic'>J</span> = 8.35), 3.40 (2 H, t, <span class='html-italic'>J</span> = 6.78), 2.94 (2 H, t, <span class='html-italic'>J</span> = 7.24), 2.63–2.60 (2 H, m), 1.92–1.86 (2 H, m), 1.77–1.71 (2 H, m), 1.67–1.60 (2 H, m), 1.53–1.47 (2 H, m), 0.92 (3 H, t, <span class='html-italic'>J</span> = 7.34); <sup>13</sup>C-NMR: 199.69, 148.45, 134.75, 128.71, 128.17, 38.20, 38.04, 33.69, 32.70, 27.95, 24.26, 23.46, 13.81.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-iso-propylphenyl)hexan-1-one</span> (<b>1e</b>). Yield: 65 %; <sup>1</sup>H-NMR: 7.89 (2 H, d, <span class='html-italic'>J</span> = 8.40), 7.30 (2 H, d, <span class='html-italic'>J</span> = 8.14), 3.42 (2 H, t, <span class='html-italic'>J</span> = 6.79), 2.99–2.93 (3 H, m), 1.94–1.88 (2 H, m), 1.79–1.73 (2 H, m), 1.56–1.49 (2 H, m), 1.26 (6 H, d, <span class='html-italic'>J</span> = 6.93); <sup>13</sup>C-NMR: 199.66, 154.50, 134.88, 128.31, 126.70, 38.21, 34.27, 33.69, 32.70, 27.96, 23.72. 23.47.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-n-butylphenyl)hexan-1-one</span> (<b>1f</b>). Yield: 44 %; <sup>1</sup>H-NMR: 7.98 (2 H, d, <span class='html-italic'>J</span> = 8.25), 7.37 (2 H, d, <span class='html-italic'>J</span> = 8.03), 3.53 (2 H, t, <span class='html-italic'>J</span> = 6.77), 3.09–3.06 (2 H, m), 2.79–2.76 (2 H, m), 2.05–2.00 (2 H, m), 1.91–1.85 (2 H, m), 1.76–1.70 (2 H, m), 1.67–1.61 (2 H, m), 1.51–1.43 (2 H, m), 1.04 (3 H, t, <span class='html-italic'>J</span> = 7.32); <sup>13</sup>C-NMR: 199.66, 148.69, 134.71, 128.66, 128.19, 38.20, 35.71, 33.68, 33.29, 32.70, 27.95, 23.46, 22.36, 13.95.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-iso-butylphenyl)hexan-1-one</span> (<b>1g</b>). Yield: 68 %; <sup>1</sup>H-NMR: 7.89 (2 H, d, <span class='html-italic'>J</span> = 8.28), 7.23 (2 H, d, <span class='html-italic'>J</span> = 8.28), 3.43 (2 H, t, <span class='html-italic'>J</span> = 6.79), 2.97 (2 H, t, <span class='html-italic'>J</span> = 7.35), 2.21 (2 H, d, <span class='html-italic'>J</span> = 7.21)<span class='html-italic'>.</span> 1.95–1.88 (3 H, m), 1.81–1.75 (2 H, m), 1.57–1.51 (2 H, m), 0.92 (6 H, t, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 199.64, 147.44, 134.79, 129.31, 128.01, 45.38, 38.17, 33.61, 32.68, 30.11, 27.93, 23.43, 22.35.</div><div class='html-p'><span class='html-italic'>6-Bromo-1-(4-tert-butylphenyl)hexan-1-one</span> (<b>1h</b>). Yield: 60 %; <sup>1</sup>H-NMR: 7.89 (2 H, d, <span class='html-italic'>J</span> = 8.50), 7.47 (2 H, d, <span class='html-italic'>J</span> = 8.52), 3.41 (2 H, t, <span class='html-italic'>J</span> = 6.79), 2.96 (2 H, t, <span class='html-italic'>J</span> = 7.35), 1.94–1.88 (2 H, m), 1.79–1.73 (2 H, m), 1.56–1.50 (2 H, m), 1.34 (9 H, s); <sup>13</sup>C-NMR: 199.60, 156.68, 134.44, 128.00, 125.53, 38.18, 35.10, 33.62, 32.68, 31.12, 27.94, 23.46.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-phenylpentan-1-one</span> (<b>1i</b>). Yield: 11 %; <sup>1</sup>H-NMR: 7.96–7.94 (2 H, m), 7.58–7.54 (1 H, m), 7.48–7.45 (2 H, m), 3.38 (2 H, t, <span class='html-italic'>J</span> = 6.62), 3.03–3.00 (2 H, m), 1.99–1.87 (4 H, m) [Lit. [<a href="#B13-molecules-13-01081" class="html-bibr">13</a>] CDCl<sub>3</sub>: 7.90–7.10 (5 H, m), 3.40 (2 H, t), 2.99 (2 H, t), 1.91 (4 H, m)]; <sup>13</sup>C-NMR: 199.53, 136.80, 133.05, 128.59, 127.97, 37.38, 33.29, 32.16, 22.72.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-methylphenyl)pentan-1-one</span> (<b>1j</b>). Yield: 57 %; <sup>1</sup>H-NMR: 7.83 (2 H, d, <span class='html-italic'>J</span> = 8.20), 7.23 (2 H, d, <span class='html-italic'>J</span> = 7.88), 3.43–3.41 (2 H, m), 2.97–2.94 (2 H, m), 2.38 (3 H, s), 1.94–1.84 (4 H, m); <sup>13</sup>C-NMR: 199.16, 143.83, 134.38, 129.29, 128.13, 37.29, 33.41, 32.25, 22.86, 21.63.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-ethylphenyl)pentan-1-one</span> (<b>1k</b>). Yield: 68 %; <sup>1</sup>H-NMR: 7.78 (2 H, d, <span class='html-italic'>J</span> = 8.03), 7.17 (2 H, d, <span class='html-italic'>J</span> = 8.03), 3.34–3.31 (2 H, m), 2.88–2.85 (2 H, m), 2.62–2.57 (2 H, m), 1.84–1.76 (4 H, m), 1.15 (3 H, t, <span class='html-italic'>J</span> = 7.53); <sup>13</sup>C-NMR: 199.19, 150.02, 134.66, 128.29, 128.15, 37.35, 33.39, 32.32, 28.98, 22.93, 15.25.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-n-propylphenyl)pentan-1-one</span> (<b>1l</b>). Yield: 55 %; <sup>1</sup>H-NMR: 7.87 (2 H, d, <span class='html-italic'>J</span> = 8.33), 7.26 (2 H, d, <span class='html-italic'>J</span> = 8.45), 3.46–3.43 (2 H, m), 3.00–2.97 (2 H, m), 2.66–2.62 (2 H, m), 1.99–1.85 (4 H, m), 1.71–1.61 (2 H, m), 0.94 (3 H, t, <span class='html-italic'>J</span> = 7.33); <sup>13</sup>C-NMR: 199.26, 148.54, 134.63, 128.72, 128.15, 38.02, 37.32, 33.38, 32.27, 24.23, 22.88, 13.77.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-iso-propylphenyl)pentan-1-one</span> (<b>1m</b>). Yield: 33 %; <sup>1</sup>H-NMR: 7.88 (2 H, d, <span class='html-italic'>J</span> = 8.20), 7.30 (2 H, d, <span class='html-italic'>J</span> = 8.20), 3.45 (2 H, t, <span class='html-italic'>J</span> = 6.62), 2.99–2.93 (3 H, m), 1.98–1.85 (4 H, m), 1.26 (6 H, d, <span class='html-italic'>J</span> = 6.94); <sup>13</sup>C-NMR: 199.21, 154.57, 134.74, 128.28, 126.70, 37.31, 34.23, 33.38, 32.25, 23.67, 22.87.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-n-butylphenyl)pentan-1-one</span> (<b>1n</b>). Yield: 37 %; <sup>1</sup>H-NMR: 7.78 (2 H, d, <span class='html-italic'>J</span> = 8.33), 7.16 (2 H, d, <span class='html-italic'>J</span> = 8.43), 3.36–3.33 (2 H, m), 2.90–2.87 (2 H, m), 2.59–2.55 (2 H, m), 1.89–1.75 (4 H, m), 1.56–1.48 (2 H, m), 1.31–1.22 (2 H, m), 0.84 (3 H, t, <span class='html-italic'>J</span> = 7.37); <sup>13</sup>C-NMR: 199.18, 148.77, 134.60, 128.67, 128.18, 37.31, 35.69, 33.38, 33.26, 32.29, 22.89, 22.35, 13.93.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-iso-butylphenyl)pentan-1-one</span> (<b>1o</b>). Yield: 51 %; <sup>1</sup>H-NMR: 7.87 (2 H, d, <span class='html-italic'>J</span> = 8.21), 7.23 (2 H, d, <span class='html-italic'>J</span> = 8.14), 3.46–3.43 (2 H, m), 3.00–2.97 (2 H, m), 2.53 (2 H, d, <span class='html-italic'>J</span> = 7.22), 1.97–1.86 (5 H, m), 0.90 (6 H, d, <span class='html-italic'>J</span> = 6.65); <sup>13</sup>C-NMR: 199.29, 147.61, 134.66, 129.37, 128.03, 45.41, 37.34, 33.42, 32.30, 30.15, 22.89, 22.38.</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-tert-butylphenyl)pentan-1-one</span> (<b>1p</b>). Yield: 58 %; <sup>1</sup>H-NMR: 7.81 (2 H, d, <span class='html-italic'>J</span> = 8.66), 7.39 (2 H, d, <span class='html-italic'>J</span> = 8.67), 3.37–3.34 (2 H, m), 2.91–2.88 (2 H, m), 1.90–1.77 (4 H, m), 1.25 (9 H, s); <sup>13</sup>C-NMR: 199.22, 156.81, 134.31, 128.02, 125.58, 37.32, 35.12, 33.38, 32.27, 31.11, 22.89.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-phenylbutan-1-one</span> (<b>1q</b>). Yield: 38 %; <sup>1</sup>H-NMR: 7.85–7.83 (2 H, m), 7.45–7.41 (1 H, m), 7.34–7.31 (2 H, m), 3.41 (2 H, t, <span class='html-italic'>J</span> = 6.38), 3.03 (2 H, t, <span class='html-italic'>J</span> = 6.93), 2.19–2.14 (2 H, m) [Lit. [<a href="#B12-molecules-13-01081" class="html-bibr">12</a>] CDCl<sub>3</sub>: 8.00–7.96 (2 H, m), 7.60–7.50 (1 H, m), 7.48–7.44 (2 H, m), 3.55 (2 H, t, <span class='html-italic'>J</span> = 6.60), 3.19 (2 H, t, <span class='html-italic'>J</span> = 6.60), 2.36–2.27 (2 H, m)]; <sup>13</sup>C-NMR: 198.36, 136.43, 132.93, 128.37, 127.72, 36.30, 33.43, 26.64.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-methylphenyl)butan-1-one</span> (<b>1r</b>). Yield: 52 %; <sup>1</sup>H-NMR: 7.85 (2 H, d, <span class='html-italic'>J</span> = 8.21), 7.23 (2 H, d, <span class='html-italic'>J</span> = 7.92), 3.51 (2 H, t, <span class='html-italic'>J</span> = 6.43), 3.11 (2 H, t, <span class='html-italic'>J</span> = 6.98), 2.38 (3 H, s), 2.29–2.24 (2 H, m); <sup>13</sup>C-NMR: 198.14, 143.80, 134.09, 129.13, 127.93, 36.23, 33.54, 26.82, 21.48.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-ethylphenyl)butan-1-one</span> (<b>1s</b>). Yield: 56 %; <sup>1</sup>H-NMR: 7.90 (2 H, d, <span class='html-italic'>J</span> = 8.24), 7.28 (2 H, d, <span class='html-italic'>J</span> = 8.21), 3.54 (2 H, t, <span class='html-italic'>J</span> = 6.44), 3.15 (2 H, t, <span class='html-italic'>J</span> = 6.98), 2.73–2.68 (2 H, m), 2.32–2.27 (2 H, m), 1.26 (3 H, t, <span class='html-italic'>J</span> = 7.68); <sup>13</sup>C-NMR: 198.32, 150.15, 134.51, 128.25, 128.14, 36.47, 33.74, 28.97, 27.04, 15.25.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-n-propylphenyl)butan-1-one</span> (<b>1t</b>). Yield: 56 %; <sup>1</sup>H-NMR: 7.91 (2 H, d, <span class='html-italic'>J</span> = 8.26), 7.28 (2 H, d, <span class='html-italic'>J</span> = 8.31), 3.55 (2 H, t, <span class='html-italic'>J</span> = 6.39), 3.16 (2 H, t, <span class='html-italic'>J</span> = 6.95), 2.67–2.64 (2 H, m), 2.33–2.28 (2 H, m), 1.71–1.64 (2 H, m), 0.96 (3 H, t, <span class='html-italic'>J</span> = 7.40); <sup>13</sup>C-NMR: 198.22, 148.50, 134.37, 128.58, 127.99, 37.87, 36.30, 33.57, 26.86, 24.08, 13.63.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-iso-propylphenyl)butan-1-one</span> (<b>1u</b>). Yield: 70 %; <sup>1</sup>H-NMR: 7.93 (2 H, d, <span class='html-italic'>J</span> = 8.34), 7.33 (2 H, d, <span class='html-italic'>J</span> = 8.26), 3.55 (2 H, t, <span class='html-italic'>J</span> = 6.38), 3.17 (2 H, t, <span class='html-italic'>J</span> = 6.93), 3.01–2.95 (1 H, m), 2.34–2.29 (2 H, m), 1.28 (6 H, d, <span class='html-italic'>J</span> = 6.93); <sup>13</sup>C-NMR: 198.39, 154.74, 134.68, 128.29, 126.73, 36.46, 34.27, 33.68, 27.03, 23.68.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-n-butylphenyl)butan-1-one</span> (<b>1v</b>). Yield: 38 %; <sup>1</sup>H-NMR: 7.80 (2 H, d, <span class='html-italic'>J</span> = 8.30), 7.17 (2 H, d, <span class='html-italic'>J</span> = 8.36), 3.45 (2 H, t, <span class='html-italic'>J</span> = 6.40), 3.05 (2 H, t, <span class='html-italic'>J</span> = 6.94), 2.58–2.55 (2 H, m), 2.22–2.17 (2 H, m), 1.55–1.49 (2 H, m), 1.30–1.22 (2 H, m), 0.84 (3 H, t, <span class='html-italic'>J</span> = 7.38); <sup>13</sup>C-NMR: 198.34, 148.90, 134.52, 128.68, 128.16, 36.46, 35.69, 33.67, 33.23, 27.04, 22.33, 13.92.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-iso-butylphenyl)butan-1-one</span> (<b>1w</b>). Yield: 51 %; <sup>1</sup>H-NMR: 7.88 (2 H, d, <span class='html-italic'>J</span> = 8.25), 7.22 (2 H, d, <span class='html-italic'>J</span> = 8.21), 3.53 (2 H, t, <span class='html-italic'>J</span> = 6.39), 3.14 (2 H, t, <span class='html-italic'>J</span> = 6.94), 2.52 (2 H, d, <span class='html-italic'>J</span> = 7.20), 2.31–2.26 (2 H, m), 1.93–1.85 (1 H, m), 0.90 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR: 198.32, 147.60, 134.45, 129.25, 127.90, 45.28, 36.35, 33.56, 29.99, 26.92, 22.23.</div><div class='html-p'><span class='html-italic'>4-Bromo-1-(4-tert-butylphenyl)butan-1-one</span> (<b>1x</b>). Yield: 47 %; <sup>1</sup>H-NMR: 7.92 (2 H, d, <span class='html-italic'>J</span> = 8.66), 7.49 (2 H, d, <span class='html-italic'>J</span> = 8.66), 3.56–3.54 (2 H, m), 3.16 (2 H, t, <span class='html-italic'>J</span> = 6.93), 2.34–2.28 (2 H, m), 1.35 (9 H, s); <sup>13</sup>C-NMR: 198.46, 156.98, 134.21, 127.99, 125.58, 36.44, 35.12, 33.66, 31.08, 27.00.</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylhexan-1-one</span> (<b>2a</b>). Yield: 22 %; mp 130 °C; IR 2942, 2363, 1680, 1596, 1448, 1318, 1180; <sup>1</sup>H-NMR: 8.45 (1 H, s), 7.96–7.94 (2 H, m), 7.59–7.45 (7 H, m), 7.31–7.27 (4 H, m), 7.20–7.17 (2 H, m), 3.46 (2 H, d, <span class='html-italic'>J</span> = 10.83), 3.00–2.97 (2 H, m), 2.85–2.83 (2 H, m), 2.62–2.59 (3 H, m), 2.17–2.14 (2 H, m), 1.79–1.76 (4 H, m), 1.61 (2 H, d, <span class='html-italic'>J</span> = 13.78), 1.44–1.41 (2 H, m); <sup>13</sup>C-NMR: 199.92, 167.85, 145.55, 136.88, 133.09, 128.63, 128.32, 128.01, 126.69, 125.58, 78.85, 52.58, 42.61, 37.98, 26.57, 23.93, 23.43; LC/MS-MS 442.11 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)hexan-1-one</span> (<b>2b</b>). Yield: 26 %; mp: 169 °C; IR: 2934, 2364, 1684, 1604, 1447, 1383, 1344, 1320, 1179; <sup>1</sup>H-NMR: 8.44 (1 H, s), 7.81 (2 H, d, <span class='html-italic'>J</span> = 8.14), 7.47 (4 H, d, <span class='html-italic'>J</span> = 7.70), 7.28–7.21 (6 H, m), 7.16–7.13 (2 H, m), 3.38 (2 H, d, <span class='html-italic'>J</span> = 11.19), 2.92 (2 H, t, <span class='html-italic'>J</span> = 7.09), 2.78–2.75 (2 H, m), 2.60–2.49 (3 H, m), 2.38 (3 H, s), 2.14–2.06 (2 H, m), 1.75–1.69 (4 H, m), 1.56 (2 H, d, <span class='html-italic'>J</span> = 13.83), 1.41–1.34 (2 H, m); <sup>13</sup>C-NMR: 199.64, 168.13, 145.62, 143.90, 134.42, 129.32, 128.32, 128.17, 126.69, 125.62, 78.90, 52.72, 42.70, 37.92, 26.68, 24.11, 23.60, 21.67; LC/MS-MS: 456.13 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)hexan-1-one</span> (<b>2c</b>). Yield: 36 %; mp: 174 °C; IR: 2939, 1685, 1605, 1447, 1383, 1345, 1320, 1286, 1148; <sup>1</sup>H-NMR: 8.48 (1 H, s), 7.86 (2 H, d, <span class='html-italic'>J</span> = 8.33), 7.51–7.49 (4 H, m), 7.30–7.26 (6 H, m), 7.19–7.16 (2 H, m), 3.38 (2 H, d, <span class='html-italic'>J</span> = 11.17), 2.94 (2 H, t, <span class='html-italic'>J</span> = 7.10), 2.77–2.68 (4 H, m), 2.63–2.45 (3 H, m), 2.15–2.05 (2 H, m), 1.78–1.69 (4 H, m), 1.58 (2 H, d, <span class='html-italic'>J</span> = 13.44), 1.43–1.36 (2 H, m), 1.25 (3 H, t, <span class='html-italic'>J</span> = 7.60); <sup>13</sup>C-NMR: 199.65, 150.05, 145.62, 134.62, 128.31, 128.26, 128.12, 126.67, 125.59, 78.92, 42.73, 37.94, 28.95, 26.72, 24.23, 23.62, 15.23; LC/MS-MS: 470.18 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)hexan-1-one</span> (<b>2d</b>). Yield: 43 %; mp: 172 °C; IR: 2940, 2395, 1686, 1605, 1447, 1384, 1345, 1318, 1286, 1177; <sup>1</sup>H-NMR: 8.27 (1 H, s), 7.64 (2 H, d, <span class='html-italic'>J</span> = 8.33), 7.30–7.28 (4 H, m), 7.09–7.03 (6 H, m), 6.96 (2 H, t, <span class='html-italic'>J</span> = 7.34), 3.17 (2 H, d, <span class='html-italic'>J</span> = 11.10), 2.73 (2 H, t, <span class='html-italic'>J</span> = 7.11), 2.56–2.53 (2 H, m), 2.44–2.23 (5 H, m), 1.95–1.85 (2 H, m), 1.57–1.35 (8 H, m), 1.22–1.16 (2 H, m), 0.73 (3 H, t, <span class='html-italic'>J</span> = 7.37); <sup>13</sup>C-NMR: 199.64, 167.99, 148.52, 145.58, 128.69, 128.28, 128.12, 126.65, 125.55, 119.97, 52.75, 43.18, 42.71, 38.00, 37.91, 26.70, 24.21, 23.58, 13.75; LC/MS-MS: 484.24 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)hexan-1-one</span> (<b>2e</b>). Yield: 43 %; mp: 154 °C; IR: 2936, 2360, 1686, 1606, 1446, 1382, 1345, 1317, 1286, 1181; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.91 (2 H, d, <span class='html-italic'>J</span> = 8.35), 7.53–7.51 (4 H, m), 7.36 (2 H, d, <span class='html-italic'>J</span> = 8.25), 7.31–7.28 (4 H, m), 7.19–7.16 (2 H, m), 3.51 (2 H, d, <span class='html-italic'>J</span> = 12.19), 3.05–2.92 (7 H, m), 2.86–2.80 (1 H, m), 1.83–1.69 (8 H, m), 1.46–1.40 (2 H, m), 1.26 (6 H, d, <span class='html-italic'>J</span> = 6.93); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 202.03, 156.18, 147.20, 136.14, 129.54, 129.47, 129.25, 129.19, 127.87, 127.80, 127.67, 127.13, 79.87, 53.91, 42.96, 38.90, 35.51, 27.33, 25.50, 25.16, 24.80, 24.09; LC/MS-MS: 484.24 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)hexan-1-one</span> (<b>2f</b>). Yield: 41 %; mp: 142 °C; IR: 2947, 2337, 1684, 1606, 1446, 1383, 1345, 1316, 1285, 1177; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.90 (2 H, d, <span class='html-italic'>J</span> = 8.27), 7.53–7.51 (4 H, m), 7.32–7.28 (6 H, m), 7.18 (2 H, t, <span class='html-italic'>J</span> = 7.32), 3.52 (2 H, d, <span class='html-italic'>J</span> = 12.35), 3.05–2.93 (6 H, m), 2.85–2.81 (1 H, m), 2.69–2.66 (2 H, m), 1.84–1.70 (8 H, m), 1.65–1.59 (2 H, m), 1.46–1.33 (4 H, m), 0.94 (3 H, t, <span class='html-italic'>J</span> = 7.34); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 204.60, 152.84, 149.71, 138.49, 132.38, 132.32, 131.92, 131.87, 131.70, 130.18, 129.63, 82.37, 56.42, 45.46, 39.13, 37.09, 29.81, 28.02, 27.66, 27.28, 25.88, 16.78; LC/MS-MS: 498.24 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)hexan-1-one</span> (<b>2g</b>). Yield: 43 %; mp: 201 °C; IR: 2940, 2357, 1684, 1605, 1446, 1385, 1345, 1286, 1177; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.91 (2 H, d, <span class='html-italic'>J</span> = 8.29), 7.54–7.52 (4 H, m), 7.32–7.29 (6 H, m), 7.20–7.17 (2 H, m), 3.52 (2 H, d, <span class='html-italic'>J</span> = 12.22), 3.06–2.94 (6 H, m), 2.86–2.81 (1 H, m), 2.56 (2 H, d, <span class='html-italic'>J</span> = 7.22), 1.96–1.72 (10 H, m), 1.48–1.42 (2 H, m), 0.92 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.20, 149.13, 147.16, 136.06, 130.54, 129.18, 127.68, 127.12, 79.88, 53.96, 46.29, 42.97, 31.35, 27.27, 25.55, 25.52, 25.18, 24.71, 22.67; LC/MS-MS: 498.23 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)hexan-1-one</span> (<b>2h</b>). Yield 56 %; mp 67 °C; IR 2962, 2359, 1677, 1603, 1447, 1271, 1191; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH) 8.48 (1 H, s), 7.92 (2 H, d, <span class='html-italic'>J</span> = 8.49), 7.54–7.51 (6 H, m), 7.31–7.28 (4 H, m), 7.18 (2 H, t, <span class='html-italic'>J</span> = 7.30), 3.53 (2 H, d, <span class='html-italic'>J</span> = 12.10), 3.07–2.96 (6 H, m), 2.86–2.81 (1 H, m), 1.84–1.74 (8 H, m), 1.47–1.41 (2 H, m), 1.34 (9 H, s); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH) 202.08, 158.30, 147.16, 135.67, 129.19, 127.65, 127.11, 126.73, 112.07, 79.86, 53.87, 42.89, 38.89, 36.00, 31.49, 27.26, 25.07, 24.80, 24.77; LC/MS-MS 498.23 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylpentan-1-one</span> (<b>2i</b>). Yield: 25 %; mp: 143 °C; IR: 3059, 2954, 2361, 1682, 1595, 1446, 1388, 1341, 1206; <sup>1</sup>H-NMR: 8.31 (1 H, s), 7.81–7.79 (2 H, m), 7.45–7.42 (1 H, m), 7.38–7.37 (4 H, m), 7.35–7.32 (2 H, m), 7.17–7.14 (4 H, m), 7.06–7.03 (2 H, m), 3.33 (2 H, d, <span class='html-italic'>J</span> = 11.67), 2.92–2.90 (2 H, m), 2.76–2.73 (2 H, m), 2.51–2.43 (3 H, m), 2.05–1.96 (2 H, m), 1.70–1.61 (4 H, m), 1.47 (2 H, d, <span class='html-italic'>J</span> = 14.19); <sup>13</sup>C-NMR: 199.46, 145.57, 136.68, 133.22, 128.66, 128.30, 127.98, 126.67, 125.58, 78.84, 52.64, 42.63, 37.60, 23.76, 21.24; LC/MS-MS: 428.10 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)pentan-1-one</span> (<b>2j</b>). Yield: 40 %; mp: 165 °C; IR: 2953, 2358, 1679, 1592, 1445, 1387, 1343, 1318, 1180; <sup>1</sup>H-NMR (CDCl<sub>3</sub> + d<sub>4</sub>-MeOH): 8.44 (1 H, s), 7.76 (2 H, d, <span class='html-italic'>J</span> = 8.28), 7.43 (4 H, d, <span class='html-italic'>J</span> = 7.28), 7.23–7.17 (6 H, m), 7.11–7.07 (2 H, m), 3.42 (2 H, d, <span class='html-italic'>J</span> = 12.05), 2.97–2.85 (4 H, m), 2.58–2.52 (3 H, m), 2.33 (3 H, s), 2.03–1.90 (2 H, m), 1.72–1.67 (4 H, m), 1.52 (2 H, d, <span class='html-italic'>J</span> = 14.56); <sup>13</sup>C-NMR (CDCl<sub>3</sub> + d<sub>4</sub>-MeOH): 199.21, 168.45, 145.32, 143.90, 133.78, 129.02, 127.93, 127.79, 126.25, 125.16, 78.01, 52.32, 42.18, 37.02, 23.13, 23.11, 23.06, 21.26, 20.79, 20.74; LC/MS-MS: 442.20 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)pentan-1-one</span> (<b>2k</b>). Yield: 30 %; mp: 167 °C; IR 2953, 2362, 1678, 1605, 1446, 1388, 1342, 1318, 1178; <sup>1</sup>H-NMR (CDCl<sub>3</sub> + d<sub>4</sub>-MeOH): 8.38 (1 H, s), 7.78 (2 H, d, <span class='html-italic'>J</span> = 8.34), 7.42 (4 H, d, <span class='html-italic'>J</span> = 9.52), 7.23–7.19 (6 H, m), 7.11–7.08 (2 H, m), 3.36 (2 H, d, <span class='html-italic'>J</span> = 11.60), 2.94–2.91 (2 H, m), 2.79–2.75 (2 H, m), 2.63 (2 H, q, <span class='html-italic'>J</span> = 7.60), 2.56–2.40 (3 H, m), 2.03 (2 H, d, <span class='html-italic'>J</span> = 12.51), 1.72–1.69 (4 H, m), 1.52 (2 H, d, <span class='html-italic'>J</span> = 13.92), 1.18 (3 H, t, <span class='html-italic'>J</span> = 7.62); <sup>13</sup>C-NMR (CDCl<sub>3</sub> + d<sub>4</sub>-MeOH): 199.16, 168.05, 150.19, 145.59, 134.44, 128.29, 128.21, 128.14, 126.65, 125.58, 78.86, 52.66, 42.67, 37.52, 30.92, 28.92, 23.87, 23.53, 21.38, 15.17; LC/MS-MS: 465.20 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)pentan-1-one</span> (<b>2l</b>). Yield: 37 %; mp: 166 °C; IR: 3059, 2954, 2357, 1679, 1605, 1446, 1384, 1341, 1315, 1179 <sup>1</sup>H-NMR: 8.37 (1 H, s), 7.77 (2 H, d, <span class='html-italic'>J</span> = 8.24), 7.42 (4 H, d, <span class='html-italic'>J</span> = 7.91), 7.22–7.16 (6 H, m), 7.10–7.07 (2 H, m), 3.34 (2 H, d, <span class='html-italic'>J</span> = 11.46), 2.93–2.90 (2 H, m), 2.75–2.73 (2 H, m), 2.57–2.42 (5 H, m), 2.06–1.97 (2 H, m), 1.68–1.48 (8 H, m), 0.86 (3 H, t, <span class='html-italic'>J</span> = 7.31); <sup>13</sup>C-NMR: 199.19, 168.15, 148.67, 145.67, 134.46, 128.74, 128.26, 128.12, 126.62, 125.61, 78.84, 52.62, 42.70, 38.00, 37.54, 24.19, 23.89, 23.57, 21.40, 13.75; LC/MS-MS: 470.22 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)pentan-1-one</span> (<b>2m</b>). Yield: 33 %; mp: 166 °C; IR: 2963, 2360, 1679, 1596, 1447, 1389, 1342, 1317, 1188; <sup>1</sup>H-NMR: 8.37 (1 H, s), 7.80 (2 H, d, <span class='html-italic'>J</span> = 8.20), 7.42 (4 H, d, <span class='html-italic'>J</span> = 8.20), 7.23–7.19 (6 H, m), 7.11–7.08 (2 H, m), 3.34 (2 H, d, <span class='html-italic'>J</span> = 11.98), 2.93–2.85 (3 H, m), 2.78–2.75 (2 H, m), 2.54–2.44 (3 H, m), 2.06–1.99 (2 H, m), 1.69–1.68 (4 H, m), 1.51 (2 H, d, <span class='html-italic'>J</span> = 13.87), 1.18 (6 H, d, <span class='html-italic'>J</span> = 6.94); <sup>13</sup>C-NMR: 199.17, 168.13, 154.75, 145.63, 134.58, 128.29, 128.26, 126.73, 125.59, 126.64, 78.85, 42.68, 37.53, 34.24, 23.86, 23.65, 21.38; LC/MS-MS: 470.30 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-n-butylphenyl)pentan-1-one</span> (<b>2n</b>). Yield: 28 %; mp: 157 °C; IR: 2955, 2365, 1679, 1604, 1447, 1387, 1341, 1314, 1248, 1183; <sup>1</sup>H-NMR: 8.37 (1 H, s), 7.77 (2 H, d, <span class='html-italic'>J</span> = 8.24), 7.42 (4 H, d, <span class='html-italic'>J</span> = 7.41), 7.22–7.17 (6 H, m), 7.11–7.07 (2 H, m), 3.37 (2 H, d, <span class='html-italic'>J</span> = 11.56), 2.94–2.91 (2 H, m), 2.79–2.76 (2 H, m), 2.60–2.45 (5 H, m), 2.09–2.00 (2 H, m), 1.71–1.65 (4 H, m), 1.57–1.49 (4 H, m), 1.32–1.24 (2 H, m), 0.85 (3 H, t, <span class='html-italic'>J</span> = 7.29); <sup>13</sup>C-NMR: 199.17, 168.09, 148.96, 145.62, 134.41, 128.70, 128.30, 128.14, 126.65, 125.59, 78.85, 52.64, 42.66, 37.52, 35.69, 33.23, 23.84, 23.51, 22.32, 21.37, 13.91; LC/MS-MS: 484.34 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-one</span> (<b>2o</b>). Yield: 29 %; mp: 173 °C; IR: 2953, 2365, 1679, 1605, 1447, 1387, 1341, 1318, 1234, 1187; <sup>1</sup>H-NMR: 8.47 (1 H, s), 7.87–7.85 (2 H, m), 7.52–7.50 (4 H, m), 7.30–7.19 (8 H, m), 3.45–3.43 (2 H, m), 3.03–3.01 (2 H, m), 2.85–2.84 (2 H, m), 2.64–2.53 (5 H, m), 2.16–2.11 (2 H, m), 1.94–1.89 (1 H, m), 1.78 (4 H, m), 1.60 (2 H, d, <span class='html-italic'>J</span> = 13.64), 0.93–0.91 (6 H, m); <sup>13</sup>C-NMR: 199.19, 167.96, 147.75, 145.56, 134.51, 129.38, 128.32, 127.99, 126.69, 125.58, 78.90, 52.69, 45.39, 42.71, 37.53, 30.10, 23.91, 23.57, 22.34, 21.41; LC/MS-MS: 484.34 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-tert-butylphenyl)pentan-1-one</span> (<b>2p</b>). Yield: 26 %; mp: 171 °C; IR: 2964, 2365, 1684, 1588, 1446, 1380, 1342, 1322, 1230, 1188; <sup>1</sup>H-NMR: 8.38 (1 H, s), 7.81–7.79 (2 H, m), 7.43–7.39 (6 H, m), 7.23–7.20 (4 H, m), 7.12–7.09 (2 H, m), 3.37–3.35 (2 H, d, <span class='html-italic'>J</span> = 10.49), 2.94–2.92 (2 H, m), 2.77–2.76 (2 H, m), 2.55–2.45 (3 H, m), 2.08–2.01 (1 H, m), 1.70 (4 H, m), 1.52 (2 H, d, <span class='html-italic'>J</span> = 14.12), 1.26 (9 H, s); <sup>13</sup>C-NMR: 199.16, 167.91, 156.99, 145.55, 134.16, 128.32, 127.97, 126.70, 125.60, 125.58, 78.90, 52.73, 52.69, 42.70, 37.54, 35.13, 31.09, 23.89, 23.58, 23.55, 21.42; LC/MS-MS: 484.31 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylbutan-1-one</span> (<b>2q</b>). Yield: 18 %; mp: 175 °C; IR: 2358, 1681, 1596, 1489, 1447, 1365, 1345, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 8.00–7.99 (2 H, m), 7.61 (1 H, t, <span class='html-italic'>J</span> = 7.41), 7.54–7.49 (6 H, m), 7.32–7.28 (4 H, m), 7.18 (2 H, t, <span class='html-italic'>J</span> = 7.36), 3.57 (2 H, d, <span class='html-italic'>J</span> = 12.26), 3.20–3.17 (2 H, m), 3.12–3.09 (2 H, m), 3.01–2.96 (2 H, m), 2.88–2.82 (1 H, m), 2.13–2.07 (2 H, m), 1.86–1.72 (4 H, m) [Lit. [<a href="#B14-molecules-13-01081" class="html-bibr">14</a>] 200 MHz, CDCl<sub>3</sub>: 7.90–7.05 (15 H, m), 2.89 (4 H, m), 2.31 (3 H, m), 1.98–1.77 (4 H, m), 1.52–1.20 (4 H, m)]; <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 198.98, 145.82, 136.52, 133.16, 128.42, 127.79, 127.71, 126.26, 125.71, 78.49, 55.98, 52.63, 47.64, 41.59, 34.77, 24.17, 18.35; LC/MS-MS: 414.18 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)butan-1-one</span> (<b>2r</b>). Yield: 13 %; mp: 191 °C; IR: 2358, 1681, 1596, 1489, 1447, 1365, 1345, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.89 (2 H, d, <span class='html-italic'>J</span> = 8.24), 7.54–7.52 (4 H, m), 7.32–7.28 (6 H, m), 7.18 (2 H, t, <span class='html-italic'>J</span> = 7.35), 3.56 (2 H, d, <span class='html-italic'>J</span> = 12.32), 3.16–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.88–2.82 (1 H, m), 2.40 (3 H, s), 2.10–2.06 (2 H, m), 1.86–1.71 (4 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.22, 147.24, 145.74, 133.45, 130.44, 129.30, 129.21, 127.67, 127.12, 79.90, 54.03, 43.00, 25.57, 21.66, 19.76, 19.70; LC/MS-MS: 428.32 (M+H<sup>+</sup>) [Lit. [<a href="#B15-molecules-13-01081" class="html-bibr">15</a>] 428 (M+H<sup>+</sup>)].</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)butan-1-one</span> (<b>2s</b>). Yield: 20 %; mp: 204 °C; IR: 2968, 2358, 1687, 1606, 1446, 1388, 1346, 1183; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.52 (1 H, s), 7.92 (2 H, d, <span class='html-italic'>J</span> = 8.33), 7.54–7.52 (4 H, m), 7.35–7.28 (6 H, m), 7.19–7.16 (2 H, m), 3.56 (2 H, d, <span class='html-italic'>J</span> = 12.34), 3.17–3.08 (4 H, m), 3.01–2.95 (2 H, m), 2.87–2.81 (1 H, m), 2.74–2.69 (2 H, m), 2.12–2.06 (2 H, m), 1.85–1.72 (4 H, m), 1.25 (3 H, t, <span class='html-italic'>J</span> = 7.62); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.19, 151.95, 147.19, 135.67, 129.40, 129.28, 129.18, 127.67, 127.12, 79.91, 54.09, 43.02, 36.08, 29.89, 25.62, 19.87, 15.70; LC/MS-MS: 442.32 (M+H<sup>+</sup>) [Lit. [<a href="#B15-molecules-13-01081" class="html-bibr">15</a>] 442 (M+H<sup>+</sup>)].</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)butan-1-one</span> (<b>2t</b>). Yield: 10 %; mp: 182 °C; IR: 3182, 2359, 1684, 1602, 1446, 1388, 1347; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.92 (2 H, d, <span class='html-italic'>J</span> = 8.31), 7.55–7.53 (4 H, m), 7.34–7.29 (6 H, m), 7.20–7.17 (2 H, t, <span class='html-italic'>J</span> = 7.35), 3.56 (2 H, d, <span class='html-italic'>J</span> = 12.20), 3.18–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.87–2.82 (1 H, m), 2.69–2.66 (2 H, m), 2.11–2.07 (2 H, m), 1.83–1.64 (6 H, m), 0.95 (3 H, t, <span class='html-italic'>J</span> = 7.38); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.21, 150.33, 147.21, 135.71, 129.91, 129.31, 129.18, 127.66, 127.12, 79.91, 57.50, 54,08, 43.04, 38.96, 36.10, 25.62, 25.37, 19.89, 19.83, 14.02; LC/MS-MS: 456.24 (M+H<sup>+</sup>) [Lit. [<a href="#B15-molecules-13-01081" class="html-bibr">15</a>] 456 (M+H<sup>+</sup>)].</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)butan-1-one</span> (<b>2u</b>). Yield: 32 %; mp: 189 °C; IR: 2960, 2366, 1691, 1596, 1446, 1345, 1189, 1062; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.52 (1 H, s), 7.92 (2 H, d, <span class='html-italic'>J</span> = 8.38), 7.54–7.52 (4 H, m), 7.37 (2 H, d, <span class='html-italic'>J</span> = 8.26), 7.30 (4 H, t, <span class='html-italic'>J</span> = 7.76), 7.19–7.16 (2 H, m), 3.56 (2 H, d, <span class='html-italic'>J</span> = 12.30), 3.17–3.08 (4 H, m), 3.00–2.95 (3 H, m), 2.87–2.81 (1 H, m), 2.11–2.06 (2 H, m), 1.85–1.72 (4 H, m), 1.27 (6 H, t, <span class='html-italic'>J</span> = 6.92); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.24, 156.44, 147.21, 135.82, 129.45, 129.19, 127.86, 127.67, 127.12, 79.90, 57.43, 54,06, 43.02, 36.10, 35.53, 25.59, 24.04, 19.80; LC/MS-MS: 456.38 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)butan-1-one</span> (<b>2v</b>). Yield: 6 %; mp: 161 °C; IR: 2963, 1687, 1607, 1448, 1362, 1182, 1139; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.91 (2 H, d, <span class='html-italic'>J</span> = 8.30), 7.54–7.52 (4 H, m), 7.33–7.28 (6 H, m), 7.18 (2 H, t, <span class='html-italic'>J</span> = 7.33), 7.19–7.16 (2 H, m), 3.55 (2 H, d, <span class='html-italic'>J</span> = 12.29), 3.16–3.06 (4 H, m), 2.98–2.93 (2 H, m), 2.87–2.81 (1 H, m), 2.70–2.67 (2 H, m), 2.12–2.06 (2 H, m), 1.85–1.71 (4 H, m), 1.65–1.59 (2 H, m), 1.40–1.32 (2 H, m), 0.94 (3 H, t, <span class='html-italic'>J</span> = 7.40); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.23, 150.56, 147.23, 135.67, 129.85, 129.32, 129.18, 127.65, 127.12, 79.92, 57.50, 54,08, 43.07, 36.61, 36.11, 34.52, 25.62, 23.33, 19.91, 14.22; LC/MS-MS: 470.17 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)butan-1-one</span> (<b>2w</b>). Yield: 20 %; mp: 155 °C; IR: 2956, 1689, 1605, 1448, 1385, 1316, 1193; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.55 (1 H, s), 7.93 (2 H, d, <span class='html-italic'>J</span> = 8.28), 7.55–7.53 (4 H, m), 7.33–7.29 (6 H, m), 7.19 (2 H, t, <span class='html-italic'>J</span> = 7.33), 3.56 (2 H, d, <span class='html-italic'>J</span> = 12.35), 3.18–3.08 (4 H, m), 3.00–2.95 (2 H, m), 2.88–2.83 (1 H, m), 2.56 (2 H, d, <span class='html-italic'>J</span> = 7.23), 2.13–2.07 (2 H, m), 1.96–1.73 (5 H, m), 0.92 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 195.87, 149.37, 147.20, 135.75, 130.54, 129.18, 127.66, 127.12, 79.92, 54.11, 46.30, 43.05, 36.10, 31.35, 25.66, 22.66, 19.90, 19.85; LC/MS-MS: 470.17 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)butan-1-one</span> (<b>2x</b>). Yield: 27 %; mp: 175 °C; IR: 2961, 2330, 1691, 1590, 1447, 1383, 1346, 1192; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.39 (1 H, s), 7.93 (2 H, d, <span class='html-italic'>J</span> = 8.58), 7.55–7.53 (6 H, m), 7.31–7.28 (4 H, m), 7.19–7.16 (2 H, m), 3.59 (2 H, d, <span class='html-italic'>J</span> = 12.22), 3.18–3.12 (4 H, m), 3.04–3.00 (2 H, m), 2.89–2.84 (1 H, m), 2.13–2.07 (2 H, m), 1.89–1.80 (2 H, m), 1.74–1.71 (2 H, m), 1.34 (9 H, s); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 200.12, 168.28, 158.52, 147.21, 135.34, 129.21, 127.67, 127.10, 126.75, 79.87, 53.88, 42.88, 36.08, 36.02, 31.49, 25.40, 19.66; LC/MS-MS: 470.03 (M+H<sup>+</sup>) [Lit. 470 (M+H<sup>+</sup>)] [<a href="#B15-molecules-13-01081" class="html-bibr">15</a>].</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylhexan-1-ol</span> (<b>3a</b>). Yield: 83 %; mp: 80 °C; IR: 2941, 2503, 1492, 1448, 1345, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 7.52 (4 H, d, <span class='html-italic'>J</span> = 7.80), 7.32–7.28 (8 H, m), 7.24–7.21 (1 H, m), 7.19–7.16 (2 H, m), 4.61–4.59 (1 H, m), 3.52 (2 H, d, <span class='html-italic'>J</span> = 12.23), 3.03–2.96 (4 H, m), 2.88–2.82 (1 H, m), 1.82–1.66 (8 H, m), 1.49–1.29 (4 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 146.97, 146.31, 129.16, 129.05, 128.12, 127.53, 126.95, 126.91, 79.65, 74.79, 58.06, 53.90, 42.67, 39.71, 27.44, 26.21, 25.61, 24.93; LC/MS-MS: 444.21 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)hexan-1-ol</span> (<b>3b</b>). Yield: 62 %; mp: 71 °C; IR: 2941, 2361, 1593, 1491, 1447, 1335, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 7.39), 7.31–7.28 (4 H, m), 7.21–7.16 (4 H, m), 7.12 (2 H, d, <span class='html-italic'>J</span> = 7.92), 4.55 (1 H, t, <span class='html-italic'>J</span> = 6.62), 3.48 (2 H, d, <span class='html-italic'>J</span> = 12.38), 2.98–2.89 (4 H, m), 2.84–2.78 (1 H, m), 2.30 (3 H, s), 1.81–1.63 (8 H, m), 1.47–1.27 (4 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 170.17, 147.20, 143.39, 137.98, 129.91, 129.20, 127.68, 127.12, 127.07, 79.88, 74.85, 53.92, 42.99, 39.82, 27.68, 26.42, 25.56, 25.53, 25.24, 21.17; LC/MS-MS: 458.21 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)hexan-1-ol</span> (<b>3c</b>). Yield: 82 %; mp: 75 °C; IR: 2936, 2364, 1595, 1447, 1359, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.53–7.51 (4 H, m), 7.31–7.27 (4 H, m), 7.22 (2 H, d, <span class='html-italic'>J</span> = 8.04), 7.19–7.14 (4 H, m), 4.56 (1 H, t, <span class='html-italic'>J</span> = 6.62), 3.48 (2 H, d, <span class='html-italic'>J</span> = 12.67), 2.99–2.90 (4 H, m), 2.85–2.79 (1 H, m), 2.63–2.59 (2 H, q, <span class='html-italic'>J</span> = 7.61), 1.83–1.63 (8 H, m), 1.47–1.27 (4 H, m), 1.21 (3 H, t, <span class='html-italic'>J</span> = 7.59); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.21, 144.55, 143.66, 129.20, 128.76, 127.67, 127.15, 127.11, 79.87, 74.87, 53.87, 42.95, 39.82, 29.57, 27.67, 26.43, 25.50, 25.18, 16.32; LC/MS-MS: 472.21 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)hexan-1-ol</span> (<b>3d</b>). Yield: 71 %; mp: 73 °C; IR: 2933, 2364, 1596, 1448, 1334, 1179, 1064; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.52–7.51 (4 H, m), 7.31–7.27 (4 H, m), 7.22 (2 H, d, <span class='html-italic'>J</span> = 8.05), 7.19–7.12 (4 H, m), 4.56 (1 H, t, <span class='html-italic'>J</span> = 6.55), 3.45 (2 H, d, <span class='html-italic'>J</span> = 12.32), 2.95–2.78 (5 H, m), 2.57–2.54 (2 H, m), 1.80–1.58 (10 H, m), 1.46–1.28 (4 H, m), 0.92 (3 H, t, <span class='html-italic'>J</span> = 7.38); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 145.80, 142.28, 141.43, 127.98, 127.76, 126.23, 125.69, 125.63, 120.00, 79.47, 73.45, 56.54, 52.53, 41.65, 38.39, 37.32, 26.28, 25.03, 24.41, 24.17, 23.88, 12.68; LC/MS-MS: 486.27 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)hexan-1-ol</span> (<b>3e</b>). Yield: 75 %; mp: 62 °C; IR: 2961, 2364, 1597, 1448, 1333, 1180, 1064; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 8.15), 7.31–7.28 (4 H, m), 7.23 (2 H, d, <span class='html-italic'>J</span> = 8.12), 7.19–7.16 (4 H, m), 4.58–4.55 (1 H, m), 3.47 (2 H, d, <span class='html-italic'>J</span> = 11.87), 2.98–2.79 (6 H, m), 1.80–1.63 (7 H, m), 1.47–1.24 (4 H, m), 1.23 (6 H, d, <span class='html-italic'>J</span> = 6.93); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 149.17, 147.19, 143.81, 129.20, 127.68, 127.29, 127.12, 79.88, 74.86, 53.91, 42.98, 39.81, 35.14, 27.68, 26.45, 25.54, 25.23, 24.54; LC/MS-MS: 486.34 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)hexan-1-ol</span> (<b>3f</b>). Yield: 55 %; mp: 64 °C; IR 2930, 2356, 1595, 1448, 1341, 1068; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 7.37), 7.31–7.27 (4 H, m), 7.22 (2 H, d, <span class='html-italic'>J</span> = 8.04), 7.19–7.12 (4 H, m), 4.56 (1 H, m), 3.44 (2 H, d, <span class='html-italic'>J</span> = 12.00), 2.93–2.76 (5 H, m), 2.58 (2 H, t, <span class='html-italic'>J</span> = 7.72), 1.79–1.54 (10 H, m), 1.46–1.29 (6 H, m), 0.93 (3 H, t, <span class='html-italic'>J</span> = 7.40); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.24, 143.66, 143.08, 129.35, 129.19, 127.67, 127.14, 79.91, 74.90, 54.01, 43.14, 39.81, 36.33, 35.07, 27.74, 26.47, 25.67, 25.38, 23.36, 14.32; LC/MS-MS: 500.45 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)hexan-1-ol</span> (<b>3g</b>). Yield: 76 %; mp: 70 °C; IR: 2953, 1596, 1447, 1339, 1168, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.55 (1 H, s), 7.53–7,52 (4 H, m), 7.32–7.29 (4 H, m), 7.25–7.17 (4 H, m), 7.11 (2 H, d, <span class='html-italic'>J</span> = 8.05), 4.59–4.57 (1 H, m), 3.48 (2 H, d, <span class='html-italic'>J</span> = 12.41), 2.98–2.79 (5 H, m), 2.47–2.45 (2 H, d, <span class='html-italic'>J</span> = 7.18), 1.87–1.64 (9 H, m), 1.49–1.29 (4 H, m), 0.90 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.17, 143.76, 141.87, 130.05, 129.18, 127.67, 127.11, 126.93, 79.89, 74.88, 53.94, 46.13, 43.01, 39.76, 31.50, 27.66, 26.43, 25.25, 22.71, 19.23; LC/MS-MS: 500.19 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>6-(4'-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-tert-butylphenyl)hexan-1-ol</span> (<b>3h</b>). Yield: 69 %; mp: 73 °C; IR: 2957, 2365, 1597, 1447, 1341, 1171, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.52 (1 H, s), 7.53–7.52 (4 H, m), 7.37 (2 H, d, <span class='html-italic'>J</span> = 8.41), 7.32–7.25 (6 H, m), 7.20–7.17 (2 H, m), 4.59–4.57 (1 H, m), 3.50 (2 H, d, <span class='html-italic'>J</span> = 12.34), 3.02–2.94 (4 H, m), 2.86–2.80 (1 H, m), 1.83–1.65 (8 H, m), 1.49–1.32 (4 H, m), 1.31 (9 H, s); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 169.85, 151.33, 147.13, 143.35, 129.20, 127.69, 127.10, 126.84, 126.16, 79.88, 74.76, 53.87, 49.04, 42.90, 39.74, 35.32, 31.85, 27.63, 26.41, 25.14; LC/MS-MS: 500.33 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylpentan-1-ol</span> (<b>3i</b>). Yield: 75 %; mp: 182 °C; IR: 2778, 2361, 1629, 1448, 1356, 1064; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.55 (2 H, s), 7.52–7.50 (4 H, m), 7.34–7.27 (8 H, m), 7.24–7.20 (1 H, m), 7.18–7.15 (2 H, m), 4.61 (1 H, t, <span class='html-italic'>J</span> = 5.78), 3.45 (2 H, d, <span class='html-italic'>J</span> = 12.37), 2.95–2.76 (5 H, m), 1.84–1.65 (8 H, m), 1.51–1.29 (3 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.20, 146.29, 129.34, 129.15, 128.32, 127.63, 127.11, 127.02, 79.89, 74.71, 53.93, 43.11, 39.53, 25.56, 25.28, 24.13; LC/MS-MS: 430.14 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)pentan-1-ol</span> (<b>3j</b>). Yield: 71 %; mp: 84 °C; IR: 3340, 2951, 2361, 1595, 1491, 1447, 1330, 1173; <sup>1</sup>H-NMR: 8.41 (1 H, s), 7.49 (4 H, d, <span class='html-italic'>J</span> = 7.53), 7.29–7.25 (4 H, m), 7.20–7.09 (6 H, m), 4.61–4.60 (1 H, m), 3.41–3.38 (2 H, m), 2.82–2.80 (2 H, m), 2.58–2.55 (3 H, m), 2.31 (3 H, s), 2.15–2.08 (2 H, m), 1.82–1.67 (4 H, m), 1.54 (2 H, d, <span class='html-italic'>J</span> = 13.11), 1.44–1.35 (2 H, m); <sup>13</sup>C-NMR: 168.26, 145.65, 141.87, 136.90, 129.04, 128.29, 126.62, 125.78, 125.59, 78.74, 73.28, 52.47, 42.43, 38.27, 23.64, 23.05, 21.12; LC/MS-MS: 444.38 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)pentan-1-ol</span> (<b>3k</b>). Yield: 80 %; mp: 70 °C; IR: 2933, 1595, 1447, 1341, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.46 (1 H, s), 7.49 (4 H, d, <span class='html-italic'>J</span> = 8.27), 7.28–7.25 (4 H, m), 7.21 (2 H, d, <span class='html-italic'>J</span> = 8.01), 7.16–7.12 (4 H, m), 4.56 (1 H, t, <span class='html-italic'>J</span> = 6.90), 3.46 (2 H, d, <span class='html-italic'>J</span> = 12.17), 2.99–2.90 (4 H, m), 2.82–2.78 (1 H, m), 2.58 (1 H, q, <span class='html-italic'>J</span> = 7.58), 1.79–1.65 (8 H, m), 1.45–1.27 (2 H, m), 1.17 (3 H, t, <span class='html-italic'>J</span> = 7.59); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 145.74, 143.24, 142.06, 127.79, 127.40, 126.28, 125.69, 120.02, 78.43, 73.19, 52.47, 41.45, 37.99, 36.34, 28.15, 23.67, 22.65, 14.91; LC/MS-MS: 458.16 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)pentan-1-ol</span> (<b>3l</b>). Yield: 64 %; mp: 83 °C; IR: 2933, 2362, 1594, 1447, 1342, 1242, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.50 (1 H, s), 7.50–7.48 (4 H, m), 7.28–7.25 (4 H, m), 7.21–7.20 (2 H, m), 7.15–7.10 (4 H, m), 4.56–4.55 (1 H, m), 3.44 (2 H, d, <span class='html-italic'>J</span> = 12.59), 2.94–2.87 (4 H, m), 2.81–2.76 (1 H, m), 2.54–2.52 (1 H, m), 1.75–1.58 (10 H, m), 1.44–1.27 (2 H, m), 0.91–0.88 (3 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.02, 143.36, 142.79, 138.87, 129.47, 129.29, 129.03, 127.51, 127.38, 126.94, 126.86, 79.69, 74.46, 53.69, 42.78, 39.24, 38.57, 25.68, 25.32, 24.98, 23.93, 13.94; LC/MS-MS: 472.23 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)pentan-1-ol</span> (<b>3m</b>). Yield: 68 %; mp: 82 °C; IR: 3337, 2956, 2298, 1597, 1447, 1385, 1179; <sup>1</sup>H-NMR: 8.40 (1 H, s), 7.49 (2 H, d, <span class='html-italic'>J</span> = 7.54), 7.30–7.23 (6 H, m), 7.19–7.17 (4 H, m), 4.66–4.63 (1 H, m), 3.47–3.45 (2 H, m), 2.90–2.86 (3 H, m), 2.63–2.59 (3 H, m), 2.21–2.17 (2 H, m), 1.82–1.68 (4 H, m), 1.59 (2 H, d, <span class='html-italic'>J</span> = 13.79). 1.51–1.41 (2 H, m), 1.23 (6 H, d, <span class='html-italic'>J</span> = 6.92); <sup>13</sup>C-NMR: 167.61, 148.08, 145.45, 142.05, 128.34, 126.71, 126.45, 125.82, 125.56, 78.82, 73.46, 42.43, 38.05, 33.79, 24.02, 23.55, 23.05; LC/MS-MS: 472.38 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-n-butylphenyl)pentan-1-ol</span> (<b>3n</b>). Yield: 71 %; IR: 2930, 2362, 1592, 1448, 1343, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.34 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 8.30), 7.31–7.27 (4 H, m), 7.23 (2 H, d, <span class='html-italic'>J</span> = 8.04), 7.19–7.12 (4 H, m), 4.58 (1 H, t, <span class='html-italic'>J</span> = 6.20), 3.49 (2 H, d, <span class='html-italic'>J</span> = 12.36), 3.02–2.79 (5 H, m), 2.58 (2 H, t, <span class='html-italic'>J</span> = 7.72), 1.83–1.66 (8 H, m), 1.60–1.48 (2 H, m), 1.31–1.29 (4 H, m), 0.92 (3 H, t, <span class='html-italic'>J</span> = 7.32); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 166.41, 145.71, 142.05, 141.77, 127.99, 127.80, 126.29, 125.69, 125.63, 78.43, 73.21, 52.43, 41.42, 37.96, 34.89, 33.65, 23.67, 22.64, 21.94, 12.89; LC/MS-MS: 486.20 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-ol</span> (<b>3o</b>). Yield: 68 %; mp: 75 °C; IR: 2952, 2504, 1593, 1447, 1345, 1186, 1067; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.36 (1 H, s), 7.53–7.50 (4 H, m), 7.31–7.27 (4 H, m), 7.24 (2 H, d, <span class='html-italic'>J</span> = 8.02), 7.19–7.16 (2 H, m), 7.11 (2 H, d, <span class='html-italic'>J</span> = 8.11), 4.59 (1 H, t, <span class='html-italic'>J</span> = 5.99), 3.49 (2 H, d, <span class='html-italic'>J</span> = 12.54), 3.03–2.80 (5 H, m), 2.44 (2 H, d, <span class='html-italic'>J</span> = 7.18), 1.86–1.67 (9 H, m), 1.50–1.29 (2 H, m), 0.88 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.12, 143.58, 141.96, 130.10, 129.20, 127.69, 127.10, 126.90, 79.84, 74.61, 53.88, 46.11, 42.82, 39.34, 31.51, 25.07, 24.06, 22.70; LC/MS-MS: 486.27 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4’-(Hydroxydiphenylmethyl)-piperidin-1-yl)-1-(4-tert-butylphenyl)pentan-1-ol</span> (<b>3p</b>). Yield: 58 %; mp: 88 °C; IR: 2950, 2359, 1597, 1447, 1345, 1033; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.46 (1 H, s), 7.52–7.50 (4 H, m), 7.36 (2 H, d, <span class='html-italic'>J</span> = 8.43), 7.31–7.25 (6 H, m), 7.19–7.16 (2 H, m), 4.60 (1 H, t, <span class='html-italic'>J</span> = 6.84), 3.49 (2 H, d, <span class='html-italic'>J</span> = 12.54), 3.02–2.94 (4 H, m), 2.86–2.80 (1 H, m), 1.84–1.67 (8 H, m), 1.49–1.32 (2 H, m), 1.29 (9 H, s); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 153.94, 149.62, 145.67, 131.73, 130.23, 130.19, 129.60, 129.36, 129.33, 128.74, 82.38, 77.04, 56.43, 45.35, 41.83, 37.85, 34.37, 27.61, 26.54; LC/MS-MS: 486.27 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-phenylbutan-1-ol</span> (<b>3q</b>). Yield: 76 %; mp: 94 °C; IR: 2778, 2361, 2339, 1595, 1448, 1356, 1064; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.53 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 7.56), 7.36–7.23 (9 H, m), 7.17 (2 H, d, <span class='html-italic'>J</span> = 7.29), 4.68–4.66 (1 H, m), 3.45–3.44 (2 H, m), 3.02–2.99 (2 H, m), 2.92–2.78 (3 H, m), 1.84–1.67 (8 H, m) [Lit. [<a href="#B14-molecules-13-01081" class="html-bibr">14</a>] 200 MHz, CDCl<sub>3</sub>: 7.67–7.11 (15 H, m), 4.60 (1 H, m), 3.43 (1 H, d, <span class='html-italic'>J</span> = 7.00), 3.12 (1 H, d, <span class='html-italic'>J</span> = 11.00), 2.94 (1 H, d, <span class='html-italic'>J</span> = 11.00), 2.51–2.34 (5 H, m), 2.15–1.74 (4 H, m), 1.62–1.44 (4 H, m)]; <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.21, 145.98, 129.43, 129.17, 128.46, 127.65, 127.09, 126.91, 79.89, 74.27, 54.03, 53.91, 43.05, 37.21, 25.57, 22.08, 21.89; LC/MS-MS: 416.21 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-methylphenyl)butan-1-ol</span> (<b>3r</b>). Yield: 45 %; mp: 97 °C; IR: 2355, 1595, 1447, 1356, 1063; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.52 (4 H, d, <span class='html-italic'>J</span> = 7.90), 7.32–7.29 (4 H, m), 7.24 (2 H, d, <span class='html-italic'>J</span> = 8.00), 7.20–7.14 (4 H, m), 4.65–4.63 (1 H, m), 3.48–3.45 (2 H, m), 3.04–3.00 (2 H, m), 2.94–2.79 (3 H, m), 2.31 (3 H, s), 1.83–1.68 (8 H, m); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 170.06, 147.18, 142.87, 138.23, 130.02, 129.18, 127.66, 127.09, 126.89, 79.89, 74.14, 54.03, 53.91, 43.02, 37.13, 25.60, 22.08, 21.89, 21.12; LC/MS-MS: 430.14 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-ethylphenyl)butan-1-ol</span> (<b>3s</b>). Yield: 41 %; mp: 99 °C; IR: 2959, 1596, 1490, 1447, 1344, 1066; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.55 (1 H, s), 7.52 (4 H, d, <span class='html-italic'>J</span> = 7.83), 7.31–7.25 (6 H, m), 7.19–7.17 (4 H, m), 4.65–4.63 (1 H, m), 3.41–3.36 (2 H, m), 2.95–2.91 (2 H, m), 2.79–2.76 (3 H, m), 2.65–2.60 (2 H, m), 1.82–1.66 (8 H, m), 1.21 (3 H, t, <span class='html-italic'>J</span> = 7.61); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 170.26, 147.31, 144.78, 143.23, 143.21, 129.17, 128.88, 127.63, 127.13, 127.01, 79.97, 74.28, 74.17, 58.31, 54.21, 54.08, 43.36, 37.38, 29.56, 25.82, 22.39, 22.19, 16.29; LC/MS-MS: 444.28 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-propylphenyl)butan-1-ol</span> (<b>3t</b>). Yield: 76 %; mp: 104 °C; IR: 2933, 2363, 1593, 1491, 1447, 1342, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.56 (1 H, s), 7.52 (4 H, d, <span class='html-italic'>J</span> = 7.74), 7.31–7.25 (6 H, m), 7.19–7.15 (4 H, m), 4.64–4.63 (1 H, m), 3.38–3.32 (2 H, m), 2.90–2.86 (2 H, m), 2.78–2.70 (3 H, m), 2.59–2.56 (2 H, m), 1.78–1.60 (8 H, m), 0.93 (3 H, t, <span class='html-italic'>J</span> = 7.35); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.35, 143.27, 143.03, 129.49, 129.12, 127.57, 127.11, 126.91, 79.98, 74.20, 58.38, 54.26, 54.12, 43.51, 38.71, 25.90, 25.79, 22.31, 14.06; LC/MS-MS: 460.23 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-propylphenyl)butan-1-ol</span> (<b>3u</b>). Yield: 69 %; mp: 173 °C; IR: 2959, 2363, 1606, 1446, 1327, 1176, 1071; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.52 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 7.62), 7.31–7.26 (6 H, m), 7.21–7.16 (4 H, m), 4.65–4.63 (1 H, m), 3.47–3.45 (2 H, m), 3.04–3.01 (2 H, m), 2.94–2.78 (4 H, m), 1.83–1.68 (8 H, m), 1.22 (6 H, t, <span class='html-italic'>J</span> = 6.93); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 149.42, 147.18, 143.27, 129.18, 127.67, 127.41, 127.08, 126.97, 79.86, 74.13, 53.97, 53.87, 49.01, 42.97, 37.06, 35.10, 25.52, 24.46, 22.01; LC/MS-MS: 458.13 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-n-butylphenyl)butan-1-ol</span> (<b>3v</b>). Yield: 65 %; mp: 175 °C; IR: 2932, 2366, 1596, 1448, 1342, 1065; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.51 (4 H, d, <span class='html-italic'>J</span> = 7.48), 7.30–7.24 (6 H, m), 7.18–7.14 (4 H, m), 4.64–4.62 (1 H, m), 3.41–3.35 (2 H, m), 2.93–2.90 (2 H, m), 2.80–2.74 (3 H, m), 2.60–2.57 (2 H, m), 1.81–1.65 (8 H, m), 1.60–1.54 (2 H, m), 1.37–1.32 (2 H, m), 0.92 (3 H, t, <span class='html-italic'>J</span> = 7.40); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.27, 143.29, 143.18, 129.45, 129.14, 127.61, 127.10, 126.92, 85.09, 79.96, 74.27, 54.08, 43.34, 37.33, 36.27, 35.01, 31.79, 25.81, 23.31, 22.37, 19.23, 14.27; LC/MS-MS: 472.20 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-(4’-(Hydroxydiphenylmethyl)piperidin-1-yl)-1-(4-iso-butylphenyl)butan-1-ol</span> (<b>3w</b>). Yield: 68 %; mp: 177 °C; IR: 2950, 2361, 1595, 1447, 1328, 1171, 1067; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.54 (1 H, s), 7.52–7,50 (4 H, d, <span class='html-italic'>J</span> = 7.42), 7.30–7.24 (6 H, m), 7.18–7.15 (2 H, m), 7.13–7.11 (2 H, m), 4.65–4.62 (1 H, m), 3.42–3.38 (2 H, m), 2.96–2.93 (2 H, m), 2.83–2.74 (3 H, m), 2.45 (2 H, d, <span class='html-italic'>J</span> = 7.18), 1.86–1.66 (9 H, m), 0.88 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 147.29, 143.32, 142.10, 130.18, 129.17, 127.64, 127.12, 126.81, 79.95, 74.27, 58.25, 54.15, 46.12, 43.29, 37.29, 31.52, 25.76, 22.71, 22.32; LC/MS-MS: 472.34 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>4-tert-Butylphenyl-6-bromohexanoate</span> (<b>4a</b>). Yield: 61 %; <sup>1</sup>H-NMR: 7.41–7.40 (2 H, d, <span class='html-italic'>J</span> = 8.59), 7.03–7.02 (2 H, d, <span class='html-italic'>J</span> = 8.77), 3.47–3.44 (2 H, t, <span class='html-italic'>J</span> = 6.72), 2.61–2.58 (2 H, t, <span class='html-italic'>J</span> = 7.38), 1.98–1.92 (2 H, m), 1.84–1.78 (2 H, m), 1.63–1.59 (2 H, m), 1.34 (9 H, s); <sup>13</sup>C-NMR: 172.06, 148.59, 148.36, 126.31, 120.84, 77.33, 77.06, 76.82, 34.49, 34.17, 33.43, 32.41, 31.44, 27.64, 24.12.</div><div class='html-p'>N-(4-tert-Butylphenyl)-6-bromohexanamide (<b>4b</b>). Yield: 71 %; <sup>1</sup>H-NMR: 7.43–7.41 (2 H, d, <span class='html-italic'>J</span> = 8.59), 7.34–7.32 (2 H, d, <span class='html-italic'>J</span> = 8.58), 3.43–3.40 (2 H, t, <span class='html-italic'>J</span> = 6.70), 2.38–2.25 (2 H, t, <span class='html-italic'>J</span> = 7.38), 1.93–1.87 (2 H, m), 1.79–1.73 (2 H, m), 1.56–1.50 (2 H, m), 1.30 (9 H, s); <sup>13</sup>C-NMR: 170.95, 147.37, 135.09, 125.80, 119.72, 38.74, 37.37, 33.53, 32.43, 31.34, 27.72, 24.70.</div><div class='html-p'><span class='html-italic'>4-tert-Butylphenyl-6-(4’-(hydroxydiphenylmethyl)pi-peridin-1-yl)hexanoate</span> (<b>5a</b>). Yield: 52 %; IR: 3398, 2962, 2359, 1749, 1591, 1509, 1448, 1347, 1207, 1172, 1147, 1108, 1017, 951, 839, 749, 702; <sup>1</sup>H-NMR: 8.46 (1 H, s), 7.54–7.53 (4 H, m), 7.41–7.39 (2 H, m), 7.30–7.29 (4 H, m), 7.18–7.17 (2 H, m), 6.99–6.98 (2 H, m), 3.50 (2 H, s), 3.04–2.82 (5 H, m), 2.60–2.59 (2 H, m), 1.83–1.70 (8 H, m), 1.47 (2 H, s), 1.30 (9 H, s); <sup>13</sup>C-NMR: 173.82, 169.06, 169.02, 149.95, 147.27, 129.25, 127.76, 127.36, 127.12, 122.12, 79.88, 53.77, 42.93, 35.38, 34.68, 31.94, 27.74, 27.14, 25.35, 24.85, 24.41, 24.03, 23.82; LC/MS-MS: 514.25 (M+H<sup>+</sup>). </div><div class='html-p'><span class='html-italic'>N-(4-tert-Butylphenyl)-6-(4-(hydroxydiphenylmethyl)piperidin-1-yl)hexanamide</span> (<b>5b</b>). Yield: 36 %; IR: 3286, 2959, 1662, 1598, 1537, 1448, 1346, 1111, 1031, 953, 839, 749, 702; <sup>1</sup>H-NMR: 8.44 (1 H, s), 7.53–7.52 (4 H, d, <span class='html-italic'>J</span> = 7.36), 7.46–7.44 (2 H, d, <span class='html-italic'>J</span> = 8.70), 7.34–7.28 (6 H, m), 7.19–7.16 (2 H, t, <span class='html-italic'>J</span> = 7.35), 3.63 (1 H, s), 3.53–3.51 (2 H, m), 3.07–2.99 (4 H, m), 2.87–2.81 (1 H, m), 2.41–2.38 (2 H, t, <span class='html-italic'>J</span> = 7.16), 1.78–1.71 (8 H, m), 1.46–1.43 (2 H, m), 1.30 (9 H, s); <sup>13</sup>C-NMR: 174.07, 148.32, 147.13, 129.20, 127.69, 127.11, 126.58, 121.09, 42.88, 42.85, 37.31, 35.25, 31.82, 27.22, 27.18, 26.06, 26.02, 24.90; LC/MS-MS: 513.27 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-Bromo-1-(4-tert-butylphenyl)hexan-1-ol</span> (<b>6a</b>). Yield: 74 %; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 7.26–7.24 (2 H, d, <span class='html-italic'>J</span> = 7.85), 7.13–7.12 (2 H, d, <span class='html-italic'>J</span> = 7.81), 4.47–4.44 (1 H, t, <span class='html-italic'>J</span> = 6.80), 3.27–3.24 (2 H, t, <span class='html-italic'>J</span> = 6.72), 2.43–2.39 (1 H, m), 1.74–1.56 (4 H, m), 1.34–1.33 (4 H, m), 1.22 (9 H, s); <sup>13</sup>C-NMR: 150.11, 141.63, 125.41, 125.08, 73.89, 38.49, 34.31, 33.64, 32.54, 31.26, 27.90, 24.86.</div><div class='html-p'><span class='html-italic'>1-(5-Bromohexyl)-4-tert-butylbenzene</span> (<b>7a</b>).</div><div class='html-p'>To a mixture of indium(III) chloride (33 mg) and <b>6a</b> (920 mg) in dry dichloromethane chlorodiphenylsilane (1.2 mL) was added dropwise. After stirring at room temperature for 3 hours the solution was hydrolyzed with a little amount of water. Diethyl ether was added, the organic layer separated and the water phase extracted with diethyl ether two times. The combined organic layers were dried, the solvent removed under reduced pressure and the raw product was purified by column chromatography (ethyl acetate/n-hexane: 1/12, followed by pure hexane). Yield: 23 %; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 7.26–7.24 (2 H, d, <span class='html-italic'>J</span> = 8.27), 7.06–7.05 (2 H, d, <span class='html-italic'>J</span> = 8.26), 3.34–3.31 (2 H, t, <span class='html-italic'>J</span> = 6.83), 2.55–2.52 (2 H, t, <span class='html-italic'>J</span> = 7.88), 1.82–1.78 (2 H, m), 1.59–1.55 (2 H, m), 1.43–1.38 (2 H, m), 1.34–1.30 (2 H, m), 1.27 (9 H, s); <sup>13</sup>C-NMR: 148.33, 139.38, 127.97, 125.08, 35.23, 34.28, 33.78, 32.73, 31.41, 31.18, 28.45, 28.02.</div><div class='html-p'><span class='html-italic'>(1-(6-(4-tert-Butylphenyl)hexyl)piperidin-4-yl)diphenylmethanol</span> (<b>8a</b>). Yield: 40 %; IR: 2933, 2363, 1662, 1596, 1491, 1447, 1343, 1172, 1067, 955, 832, 749, 702; <sup>1</sup>H-NMR: 7.46–7.45 (4 H, d, <span class='html-italic'>J</span> = 8.49), 7.26–7.22 (6 H, t, <span class='html-italic'>J</span> = 8.45), 7.14–7.11 (2 H, t, <span class='html-italic'>J</span> = 7.31), 7.05–7.03 (2 H, d, <span class='html-italic'>J</span> = 8.26), 3.43–3.41 (2 H, d, <span class='html-italic'>J</span> = 11.05), 2.81–2.77 (2 H, m), 2.58–2.55 (2 H, m), 2.52–2.49 (2 H, t, <span class='html-italic'>J</span> = 7.85), 2.15–2.13 (2 H, m), 1.68–1.67 (2 H, m), 1.58–1.55 (4 H, m), 1.31–1.29 (4 H, m), 1.27 (9 H, s); <sup>13</sup>C-NMR: 148.45, 145.48, 139.22, 128.27, 127.96, 126.65, 125.54, 125.12, 78.78, 52.52, 52.5, 52.46, 52.45, 45.38, 42.50, 35.13, 34.30, 31.39, 31.09, 28.72, 26.79, 23.76, 23.31, 23.27; LC/MS-MS: 485.00 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(piperidin-1-yl)pentan-1-one</span> (<b>9a</b>). Yield: 78 %; mp: 143 °C; IR: 2955, 2869, 1739, 1676, 1604, 1453, 1368, 1273, 1184, 1022; <sup>1</sup>H-NMR: 7.93–7.91 (2 H, d, <span class='html-italic'>J</span> = 8.31), 7.30–7.28 (2 H, d, <span class='html-italic'>J</span> = 8.25), 3.13–3.07 (4 H, m), 2.56–2.55 (2 H, d, <span class='html-italic'>J</span> = 7.23), 1.95–1.68 (12 H, m), 1.35–1.32 (1 H, m), 0.92–0.91 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR: 201.45, 149.18, 136.01, 130.53, 129.21, 64.32, 64.29, 58.04, 54.22, 52.98, 46.31, 38.41, 31.35, 24.60, 24.27, 22.82, 22.69, 22.15, 16.65, 16.60; LC/MS-MS: 302.93 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(4-methylpiperidin-1-yl)pentan-1-one</span> (<b>9b</b>). Yield: 21 %; IR: 2956, 2361, 1679, 1605, 1457, 1414, 1369, 1336, 1182, 977, 855, 759; <sup>1</sup>H-NMR: 7.88–7.86 (2 H, d, <span class='html-italic'>J</span> = 8.24), 7.26–7.24 (2 H, d, <span class='html-italic'>J</span> = 8.19), 3.52–3.51 (2 H, m), 3.06–3.03 (2 H, t, <span class='html-italic'>J</span> = 6.84), 2.99–2.96 (2 H, m), 2.64–2.54 (4 H, m), 1.93–1.75 (9 H, m), 1.63–1.62 (1 H, m), 1.04–1.02 (3 H, d, <span class='html-italic'>J</span> = 6.37), 0.93–0.92 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 199.10, 147.76, 134.45, 129.31, 127.96, 45.36, 37.37, 30.07, 23.41, 22.31, 21.19; LC/MS-MS: 315.94 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(4-hydroxypiperidin-1-yl)-pentan-1-one</span> (<b>9c</b>). Yield: 68 %; IR: 3345, 2954, 2495, 1735, 1679, 1605, 1465, 1414, 1372, 1239, 1181, 1042, 978, 852, 763; <sup>1</sup>H-NMR: 7.90–7.88 (2 H, d, <span class='html-italic'>J</span> = 8.27), 7.26–7.25 (2 H, d, <span class='html-italic'>J</span> = 8.20), 3.93 (1 H, s), 3.38 (2 H, s), 3.19–3.05 (5 H, m), 2.52–2.51 (2 H, d, <span class='html-italic'>J</span> = 7.21), 2.06–2.03 (2 H, m), 1.89–1.73 (8 H, m), 0.88–0.87 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR: 201.44, 149.14, 136.02, 130.54, 129.23, 71.13, 57.71, 46.32, 38.47, 31.83, 31.35, 24.77, 22.72, 22.13, 20.94; LC/MS-MS: 318.11 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4-Benzylpiperidin-1-yl)-1-(4-iso-butylphenyl) pentan-1-one</span> (<b>9d</b>). Yield: 34 %; mp: 143 °C; IR: 3454, 2931, 1682, 1605, 1455, 1241, 1112; <sup>1</sup>H-NMR: 7.86–7.84 (2 H, d, <span class='html-italic'>J</span> = 8.26), 7.27–7.10 (7 H, m), 7.95–7.92 (2 H, m), 2.86 (2 H, d, <span class='html-italic'>J</span> = 11.65), 2.51–2.50 (4 H, d, <span class='html-italic'>J</span> = 7.21), 2.33–2.30 (2 H, m), 1.90–1.80 (3 H, m), 1.80–1.69 (2 H, m), 1.61–1.46 (5 H, m), 1.32–1.20 (2 H, m), 0.89–0.88 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 199.89, 147.24, 140.66, 134.76, 129.18, 129.03, 128.05, 127.98, 125.66, 77.01, 70.54, 58.67, 53.90, 45.30, 43.18, 38.25, 37.91, 32.15, 30.02, 26.69, 22.52, 22.27; LC/MS-MS: 392.07 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(piperidin-1-yl)pentan-1-ol</span> (<b>10a</b>). Yield: 94 %; mp: 64 °C; IR: 3386, 2952, 1587, 1446, 1347, 1018; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 8.55 (1 H, s), 7.25–7.24 (2 H, d, <span class='html-italic'>J</span> = 8.01), 7.12–7.10 (2 H, d, <span class='html-italic'>J</span> = 8.36), 4.60–4.58 (1 H, m), 3.31–2.98 (3 H, m), 2.85–2.82 (2 H, m), 2.46–2.45 (2 H, d, <span class='html-italic'>J</span> = 7.18), 1.87–1.61 (10 H, m), 1.48–1.28 (3 H, m), 0.90–0.88 (2 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 170.38, 143.64, 141.89, 130.07, 126.92, 74.61, 58.69, 54.46, 46.13, 31.50, 25.46, 25.43, 24.26, 24.15, 23.40, 22.70; LC/MS-MS: 306.92 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(4-methylpiperidin-1-yl)pentan-1-ol</span> (<b>10b</b>). Yield: 57 %; IR: 3349, 2953, 2667, 1717, 1594, 1458, 1177, 1051, 948, 848; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 7.23–7.21 (2 H, d, <span class='html-italic'>J</span> = 8.01), 7.11–7.09 (2 H, d, <span class='html-italic'>J</span> = 7.82), 3.54–3.53 (2 H, m), 2.92–2.90 (2 H, m), 2.56–2.54 (2 H, m), 2.45–2.44 (2 H, d, <span class='html-italic'>J</span> = 7.15), 1.87–1.70 (10 H, m), 1.50–1.39 (3 H, m), 1.02–1.01 (3 H, d, <span class='html-italic'>J</span> = 6.47), 0.89–0.88 (6 H, d, <span class='html-italic'>J</span> = 6.61); <sup>13</sup>C-NMR: 141.75, 141.05, 129.21, 125.55, 73.65, 57.35, 52.99, 45.08, 37.98, 30.19, 23.04, 22.36, 20.97; LC/MS-MS: 318.04 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-(4-hydroxypiperidin-1-yl)-pentan-1-ol</span> (<b>10c</b>). Yield: 47 %; IR: 3357, 2950, 2868, 2670, 1466, 1383, 1040, 973, 849, 802, 609; <sup>1</sup>H-NMR: 7.28–7.27 (2 H, d, <span class='html-italic'>J</span> = 8.01), 7.14–7.13 (2 H, d, <span class='html-italic'>J</span> = 8.01), 4.64–4.62 (1 H, t, <span class='html-italic'>J</span> = 7.19), 4.10–3.56 (2 H, m), 3.37 (1 H, s), 3.25 (1 H, s), 3.09–3.06 (2 H, t, <span class='html-italic'>J</span> = 8.17), 2.48–2.47 (2 H, d, <span class='html-italic'>J</span> = 7.17), 2.12–1.77 (10 H, m), 1.52–1.38 (2 H, m), 0.91–0.90 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 143.61, 141.94, 130.10, 126.93, 74.62, 52.21, 46.13, 39.39, 31.51, 30.98, 24.07, 22.72; LC/MS-MS: 319.93 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(4-Benzylpiperidin-1-yl)-1-(4-iso-butylphenyl) pentan-1-ol</span> (<b>10d</b>). Yield: 45 %; mp: 64 °C; IR: 2929, 2361, 1454, 1275; <sup>1</sup>H-NMR (d<sub>4</sub>-MeOH): 7.30–7.17 (7 H, m), 7.12–7.10 (2 H, d, <span class='html-italic'>J</span> = 7.99), 7.19–7.12 (4 H, m), 4.61–4.59 (1 H, m), 3.50–3.49 (2 H, m), 3.03–2.87 (4 H, m), 2.62–2.61 (2 H, d, <span class='html-italic'>J</span> = 7.17), 2.62–2.61 (2 H, m), 1.89–1.71 (8 H, m), 1.52–1.47 (4 H, m), 0.89–0.88 (2 H, d, <span class='html-italic'>J</span> = 6.05); <sup>13</sup>C-NMR (d<sub>4</sub>-MeOH): 143.59, 141.95, 140.50, 130.19, 130.10, 129.50, 127.40, 126.91, 74.61, 46.12, 39.36, 31.51, 25.10, 24.07, 22.71; LC/MS-MS: 394.24 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-morpholinopentan-1-one</span> (<b>11a</b>). Yield: 63 %; IR: 2867, 1681, 1606, 1466, 1353, 1251, 1182, 1114, 988, 949, 861, 734; <sup>1</sup>H-NMR: 7.85–7.83 (2 H, d, <span class='html-italic'>J</span> = 8.21), 7.22–7.20 (2 H, d, <span class='html-italic'>J</span> = 8.14), 3.88–3.86 (4 H, t, <span class='html-italic'>J</span> = 4.76), 3.00–2.98 (2 H, t, <span class='html-italic'>J</span> = 6.22), 2.90 (4 H, s), 2.79–2.76 (2 H, t, <span class='html-italic'>J</span> = 7.28), 2.52–2.50 (2 H, d, <span class='html-italic'>J</span> = 7.19), 1.89–1.87 (1 H, m), 1.76–1.75 (4 H, m), 0.89–0.88 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 199.68, 147.25, 134.66, 129.14, 127.88, 70.57, 66.73, 58.56, 53.58, 45.24, 38.06, 29.96, 25.97, 22.02, 22.14; LC/MS-MS: 304.12 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(4-iso-Butylphenyl)-5-morpholinopentan-1-ol</span> (<b>12a</b>). Yield: 26 %; IR: 3422, 2952, 2868, 2465, 1722, 1599, 1514, 1466, 1366, 1264, 1105, 977, 849, 803, 620 <sup>1</sup>H-NMR: 7.26–7.24 (2 H, d, <span class='html-italic'>J</span> = 8.00), 7.13–7.11 (2 H, d, <span class='html-italic'>J</span> = 8.03), 4.62–4.60 (1 H, m), 3.89 (4 H, s), 3.20 (4 H, s), 3.06–3.03 (2 H, t, <span class='html-italic'>J</span> = 8.31), 2.47–2.45 (2 H, d, <span class='html-italic'>J</span> = 7.18), 1.84–1.74 (5 H, m), 1.49–1.35 (2 H, m), 0.90–0.88 (6 H, d, <span class='html-italic'>J</span> = 6.63) <sup>13</sup>C-NMR: 143.62, 141.94, 130.10, 126.92, 74.63, 71.51, 65.28, 58.56, 53.25, 46.13, 45.60, 39.43, 31.51, 24.81, 24.00, 22.71 LC/MS-MS: 306.08 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>1-(5-(4-iso-Butylphenyl)-5-oxopentyl)piperidin-4-one</span> (<b>13a</b>). Yield: 3 %; IR: 2955, 2869, 2808, 1716, 1678, 1606, 1570, 1466, 1307, 1275, 1183, 954, 846, 796; <sup>1</sup>H-NMR: 7.93–7.90 (2 H, m), 7.30–7.28 (2 H, m), 2.79–2.76 (2 H, t, <span class='html-italic'>J</span> = 6.16), 2.56–2.42 (9 H, m), 1.93–1.90 (1 H, m), 1.78–1.60 (7 H, m), 0.92–0.91 (6 H, d, <span class='html-italic'>J</span> = 6.63); <sup>13</sup>C-NMR: 199.42, 129.34, 127.99, 70.48, 56.68, 52.04, 45.41, 39.37, 37.67, 30.04, 22.27, 21.65; LC/MS-MS: 316.15 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(3-(Hydroxydiphenylmethyl)pyrrolidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-one</span> (<b>15a</b>). Yield: 36 %; IR: 2957, 1679, 1605, 1448, 1367, 1182, 984, 751, 700; <sup>1</sup>H-NMR: 7.79–7.77 (2 H, d, <span class='html-italic'>J</span> = 8.15), 7.43–7.40 (4 H, t, <span class='html-italic'>J</span> = 8.27), 7.27–7.22 (4 H, m), 7.18–7.14 (4 H, m), 3.75–3.72 (1 H, m), 3.07–2.92 (8 H, m), 2.49–2.47 (2 H, d, <span class='html-italic'>J</span> = 7.19), 2.16–1.99 (2 H, m), 1.86–1.84 (1 H, m), 1.72–1.69 (4 H, m), 0.87–0.85 (6 H, d, <span class='html-italic'>J</span> = 6.62); <sup>13</sup>C-NMR: 199.11, 147.86, 145.41, 134.32, 129.37, 128.65, 128.46, 127.97, 127.91, 127.04, 125.51, 125.45, 78.48, 55.24, 54.54, 45.61, 45.36, 37.28, 30.07, 25.56, 25.13, 22.30, 20.89; LC/MS-MS: 470.10 (M+H<sup>+</sup>).</div><div class='html-p'><span class='html-italic'>5-(3-(Hydroxydiphenylmethyl)pyrrolidin-1-yl)-1-(4-iso-butylphenyl)pentan-1-ol</span> (<b>16a</b>). Yield: 48 %; IR: 3351, 2954, 2373, 1597, 1448, 1338, 1176, 1107, 1067, 1034, 850, 750, 703; <sup>1</sup>H-NMR: 7.45–7.42 (4 H, t, <span class='html-italic'>J</span> = 7.67), 7.29–7.24 (4 H, m), 7.19–7.16 (4 H, m), 7.08–7.06 (2 H, d, <span class='html-italic'>J</span> = 7.97), 4.62–4.59 (1 H, m), 3.77–3.74 (1 H, m), 2.91–2.88 (6 H, m), 2.43–2.42 (2 H, d, <span class='html-italic'>J</span> = 7.14), 2.19–2.15 (2 H, m), 1.83–1.79 (1 H, m), 1.76–1.64 (4 H, m), 1.46–1.35 (2 H, m), 0.87–0.86 (6 H, d, <span class='html-italic'>J</span> = 6.61); <sup>13</sup>C-NMR: 145.66, 141.83, 141.02, 129.20, 128.63, 128.47, 127.19, 127.07, 125.58, 125.52, 125.49, 78.49, 73.66, 61.84, 54.56, 54.38, 45.09, 37.95, 30.20, 25.63, 25.32, 22.91, 22.37; LC/MS-MS: 472.20 (M+H<sup>+</sup>).</div></section></section></section> </div> <div class="html-back"> <section id='html-ack' class='html-ack'><h2 >Acknowledgements</h2><div class='html-p'>We thank the Deutsche Forschungsgemeinschaft (DFG) for the grants given to Marcel Holzer and Sigrid Ziegler (KFO129) and the Fonds der Chemischen Industrie for financial support. Furthermore we thank Susanne Reinhardt for the syntheses of compounds <b>9a</b>, <b>9d</b>, <b>10a</b> and <b>10d</b>.</div></section><section id='html-references_list'><h2>References and Notes</h2><ol class='html-xx'><li id='B1-molecules-13-01081' class='html-x' data-content='1.'>Chisari, F. V. Unscrambling hepatitis C virus-host interactions. <span class='html-italic'>Nature</span> <b>2005</b>, <span class='html-italic'>436</span>, 930–932. 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Licensee Molecular Diversity Preservation International, Basel, Switzerland. This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( <a href='http://creativecommons.org/licenses/by/3.0/' target='_blank' rel="noopener noreferrer" >http://creativecommons.org/licenses/by/3.0/</a>).</p></section> </div> </div> <div class="additional-content"> <h2><a name="cite"></a>Share and Cite</h2> <div class="social-media-links" style="text-align: left;"> <a href="/cdn-cgi/l/email-protection#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" title="Email"> <i class="fa fa-envelope-square" style="font-size: 30px;"></i> </a> <a href="https://twitter.com/intent/tweet?text=Identification+of+Terfenadine+as+an+Inhibitor+of+Human+CD81-Receptor+HCV-E2+Interaction%3A+Synthesis+and+Structure+Optimization&hashtags=mdpimolecules&url=https%3A%2F%2Fwww.mdpi.com%2F2816&via=Molecules_MDPI" onclick="windowOpen(this.href,600,800); 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Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em> <b>2008</b>, <em>13</em>, 1081-1110. https://doi.org/10.3390/molecules13051081 </p> <div style="display: block"> <b>AMA Style</b><br> <p> Holzer M, Ziegler S, Albrecht B, Kronenberger B, Kaul A, Bartenschlager R, Kattner L, Klein CD, Hartmann RW. Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em>. 2008; 13(5):1081-1110. https://doi.org/10.3390/molecules13051081 </p> <b>Chicago/Turabian Style</b><br> <p> Holzer, Marcel, Sigrid Ziegler, Beatrice Albrecht, Bernd Kronenberger, Artur Kaul, Ralf Bartenschlager, Lars Kattner, Christian D. Klein, and Rolf W. Hartmann. 2008. "Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization" <em>Molecules</em> 13, no. 5: 1081-1110. https://doi.org/10.3390/molecules13051081 </p> <b>APA Style</b><br> <p> Holzer, M., Ziegler, S., Albrecht, B., Kronenberger, B., Kaul, A., Bartenschlager, R., Kattner, L., Klein, C. D., & Hartmann, R. W. (2008). Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em>, <em>13</em>(5), 1081-1110. https://doi.org/10.3390/molecules13051081 </p> </div> </div> <h2><a name="metrics"></a>Article Metrics</h2> <div class="row"> <div class="small-12 columns"> <div id="loaded_cite_count" style="display:none">No</div> <div id="framed_div_cited_count" class="in-tab" style="display: none; overflow: auto;"></div> <div id="loaded" style="display:none">No</div> <div id="framed_div" class="in-tab" style="display: none; margin-top: 10px;"></div> </div> <div class="small-12 columns"> <div id="article_stats_div" style="display: none; margin-bottom: 1em;"> <h3>Article Access Statistics</h3> <div id="article_stats_swf" ></div> For more information on the journal statistics, click <a href="/journal/molecules/stats">here</a>. <div class="info-box"> Multiple requests from the same IP address are counted as one view. </div> </div> </div> </div> </div> </div> </article> </div> </div></div> <div class="webpymol-controls webpymol-controls-template" style="margin-top: 10px; display: none;"> <a class="bzoom">Zoom</a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="borient"> Orient </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="blines"> As Lines </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bsticks"> As Sticks </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bcartoon"> As Cartoon </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bsurface"> As Surface </a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bprevscene">Previous Scene</a> <span style="display: inline-block; margin-left: 5px; margin-right: 5px;">|</span> <a class="bnextscene">Next Scene</a> </div> <div id="scifeed-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="recommended-articles-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="author-biographies-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="modalTitle" aria-hidden="true" role="dialog"> </div> <div id="cite-modal" class="reveal-modal reveal-modal-new" data-reveal aria-labelledby="Captcha" aria-hidden="true" role="dialog"> <div class="row"> <div class="small-12 columns"> <h2 style="margin: 0;">Cite</h2> </div> <div class="small-12 columns">  <form style="margin:0; padding:0; display:inline;" name="export-bibtex" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="1408"> <input type="hidden" name="export_format_top" value="bibtex"> <input type="hidden" name="export_submit_top" value=""> </form>  <form style="margin:0; padding:0; display:inline;" name="export-endnote" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="1408"> <input type="hidden" name="export_format_top" value="endnote_no_abstract"> <input type="hidden" name="export_submit_top" value=""> </form>  <form style="margin:0; padding:0; display:inline;" name="export-ris" method="POST" action="/export"> <input type="hidden" name="articles_ids[]" value="1408"> <input type="hidden" name="export_format_top" value="ris"> <input type="hidden" name="export_submit_top" value=""> </form> <div> Export citation file: <a href="javascript:window.document.forms['export-bibtex'].submit()">BibTeX</a> | <a href="javascript:window.document.forms['export-endnote'].submit()">EndNote</a> | <a href="javascript:window.document.forms['export-ris'].submit()">RIS</a> </div> </div> <div class="small-12 columns"> <div class="in-tab"> <div><b>MDPI and ACS Style</b></div> <p> Holzer, M.; Ziegler, S.; Albrecht, B.; Kronenberger, B.; Kaul, A.; Bartenschlager, R.; Kattner, L.; Klein, C.D.; Hartmann, R.W. Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em> <b>2008</b>, <em>13</em>, 1081-1110. https://doi.org/10.3390/molecules13051081 </p> <div style="display: block"> <b>AMA Style</b><br> <p> Holzer M, Ziegler S, Albrecht B, Kronenberger B, Kaul A, Bartenschlager R, Kattner L, Klein CD, Hartmann RW. Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em>. 2008; 13(5):1081-1110. https://doi.org/10.3390/molecules13051081 </p> <b>Chicago/Turabian Style</b><br> <p> Holzer, Marcel, Sigrid Ziegler, Beatrice Albrecht, Bernd Kronenberger, Artur Kaul, Ralf Bartenschlager, Lars Kattner, Christian D. Klein, and Rolf W. Hartmann. 2008. "Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization" <em>Molecules</em> 13, no. 5: 1081-1110. https://doi.org/10.3390/molecules13051081 </p> <b>APA Style</b><br> <p> Holzer, M., Ziegler, S., Albrecht, B., Kronenberger, B., Kaul, A., Bartenschlager, R., Kattner, L., Klein, C. D., & Hartmann, R. W. (2008). Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization. <em>Molecules</em>, <em>13</em>(5), 1081-1110. https://doi.org/10.3390/molecules13051081 </p> </div> </div> </div> </div> <a class="close-reveal-modal" aria-label="Close"> <i class="material-icons">clear</i> </a> </div> </div> </div> </div> </div> </section> <div id="footer"> <div class="journal-info"> <span> <em><a class="Var_JournalInfo" href="/journal/molecules">Molecules</a></em>, EISSN 1420-3049, Published by MDPI </span> <div class="large-right"> <span> <a href="/rss/journal/molecules" class="rss-link">RSS</a> </span> <span> <a href="/journal/molecules/toc-alert">Content Alert</a> </span> </div> </div> <div class="row full-width footer-links" data-equalizer="footer" data-equalizer-mq="small"> <div class="large-2 large-push-4 medium-3 small-6 columns" data-equalizer-watch="footer"> <h3> Further Information </h3> <a href="/apc"> Article Processing Charges 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Identification of Terfenadine as an Inhibitor of Human CD81-Receptor HCV-E2 Interaction: Synthesis and Structure Optimization