Design, Synthesis and Biological Evaluation of Novel Piperazine Derivatives as CCR5 Antagonists
Identifieur interne : 001383 ( Pmc/Curation ); précédent : 001382; suivant : 001384Design, Synthesis and Biological Evaluation of Novel Piperazine Derivatives as CCR5 Antagonists
Auteurs : Tao Liu [République populaire de Chine] ; Zhiyong Weng [République populaire de Chine] ; Xiaowu Dong [République populaire de Chine] ; Linjie Chen [République populaire de Chine] ; Ling Ma [République populaire de Chine] ; Shan Cen [République populaire de Chine] ; Naiming Zhou [République populaire de Chine] ; Yongzhou Hu [République populaire de Chine]Source :
- PLoS ONE [ 1932-6203 ] ; 2013.
Abstract
By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC50 values in low micromolar level. Among evaluated compounds,
Url:
DOI: 10.1371/journal.pone.0053636
PubMed: 23308267
PubMed Central: 3538727
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Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Linjie" sort="Chen, Linjie" uniqKey="Chen L" first="Linjie" last="Chen">Linjie Chen</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Ma, Ling" sort="Ma, Ling" uniqKey="Ma L" first="Ling" last="Ma">Ling Ma</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, 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Derivatives as CCR5 Antagonists</title><author><name sortKey="Liu, Tao" sort="Liu, Tao" uniqKey="Liu T" first="Tao" last="Liu">Tao Liu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Weng, Zhiyong" sort="Weng, Zhiyong" uniqKey="Weng Z" first="Zhiyong" last="Weng">Zhiyong Weng</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Dong, Xiaowu" sort="Dong, Xiaowu" uniqKey="Dong X" first="Xiaowu" last="Dong">Xiaowu Dong</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Chen, Linjie" sort="Chen, Linjie" uniqKey="Chen L" first="Linjie" last="Chen">Linjie Chen</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Ma, Ling" sort="Ma, Ling" uniqKey="Ma L" first="Ling" last="Ma">Ling Ma</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Peking Union Medical College, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Cen, Shan" sort="Cen, Shan" uniqKey="Cen S" first="Shan" last="Cen">Shan Cen</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Peking Union Medical College, Beijing, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Peking Union Medical College, Beijing</wicri:regionArea></affiliation></author><author><name sortKey="Zhou, Naiming" sort="Zhou, Naiming" uniqKey="Zhou N" first="Naiming" last="Zhou">Naiming Zhou</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author><author><name sortKey="Hu, Yongzhou" sort="Hu, Yongzhou" uniqKey="Hu Y" first="Yongzhou" last="Hu">Yongzhou Hu</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China</addr-line></nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS ONE</title><idno type="eISSN">1932-6203</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC<sub>50</sub> values in low micromolar level. Among evaluated compounds, <bold>23 h</bold> was found to be a CCR5 antagonist with an IC<sub>50</sub> value of 6.29 µM and an anti-HIV-1 inhibitor with an IC<sub>50</sub> value of 0.44 µM.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Yerly, S" uniqKey="Yerly S">S Yerly</name></author><author><name sortKey="Kaiser, L" uniqKey="Kaiser L">L Kaiser</name></author><author><name sortKey="Race, E" uniqKey="Race E">E Race</name></author><author><name sortKey="Bru, Jp" uniqKey="Bru J">JP Bru</name></author><author><name sortKey="Clavel, F" uniqKey="Clavel F">F Clavel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Combadiere, C" uniqKey="Combadiere C">C Combadiere</name></author><author><name sortKey="Ahuja, Sk" uniqKey="Ahuja S">SK Ahuja</name></author><author><name sortKey="Tiffany, Hl" uniqKey="Tiffany H">HL Tiffany</name></author><author><name sortKey="Murphy, Pm" uniqKey="Murphy P">PM Murphy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Deng, H" uniqKey="Deng H">H Deng</name></author><author><name sortKey="Liu, R" uniqKey="Liu R">R Liu</name></author><author><name sortKey="Ellmeier, W" uniqKey="Ellmeier W">W Ellmeier</name></author><author><name sortKey="Choe, S" uniqKey="Choe S">S Choe</name></author><author><name sortKey="Unutmaz, D" uniqKey="Unutmaz D">D Unutmaz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rodger, Dm" uniqKey="Rodger D">DM Rodger</name></author><author><name sortKey="Richard, Mn" uniqKey="Richard M">MN Richard</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takashima, K" uniqKey="Takashima K">K Takashima</name></author><author><name sortKey="Miyake, H" uniqKey="Miyake H">H Miyake</name></author><author><name sortKey="Kanzaki, N" uniqKey="Kanzaki N">N Kanzaki</name></author><author><name sortKey="Tagawa, Y" uniqKey="Tagawa Y">Y Tagawa</name></author><author><name sortKey="Wang, X" uniqKey="Wang X">X Wang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nishikawa, M" uniqKey="Nishikawa M">M Nishikawa</name></author><author><name sortKey="Takashima, K" uniqKey="Takashima K">K Takashima</name></author><author><name sortKey="Nishi, T" uniqKey="Nishi T">T Nishi</name></author><author><name sortKey="Furuta, Ra" uniqKey="Furuta R">RA Furuta</name></author><author><name sortKey="Kanzaki, N" uniqKey="Kanzaki N">N Kanzaki</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kondru, R" uniqKey="Kondru R">R Kondru</name></author><author><name sortKey="Zhang, J" uniqKey="Zhang J">J Zhang</name></author><author><name sortKey="Ji, Ch" uniqKey="Ji C">CH Ji</name></author><author><name sortKey="Mirzadegan, T" uniqKey="Mirzadegan T">T Mirzadegan</name></author><author><name sortKey="Rotstein, D" uniqKey="Rotstein D">D Rotstein</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Feng, Dz" uniqKey="Feng D">DZ Feng</name></author><author><name sortKey="Song, Yl" uniqKey="Song Y">YL Song</name></author><author><name sortKey="Jiang, Xh" uniqKey="Jiang X">XH Jiang</name></author><author><name sortKey="Chen, L" uniqKey="Chen L">L Chen</name></author><author><name sortKey="Long, Yq" uniqKey="Long Y">YQ Long</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jiang, Xh" uniqKey="Jiang X">XH Jiang</name></author><author><name sortKey="Song, Yl" uniqKey="Song Y">YL Song</name></author><author><name sortKey="Long, Yq" uniqKey="Long Y">YQ Long</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Torre, O" uniqKey="Torre O">O Torre</name></author><author><name sortKey="Gotor Fernandez, V" uniqKey="Gotor Fernandez V">V Gotor-Fernández</name></author><author><name sortKey="Gotor, V" uniqKey="Gotor V">V Gotor</name></author></analytic></biblStruct><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Lj" uniqKey="Chen L">LJ Chen</name></author><author><name sortKey="Zhang, Yp" uniqKey="Zhang Y">YP Zhang</name></author><author><name sortKey="Li, G" uniqKey="Li G">G Li</name></author><author><name sortKey="Huang, Hs" uniqKey="Huang H">HS Huang</name></author><author><name sortKey="Zhou, Nm" uniqKey="Zhou N">NM Zhou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Coakley, E" uniqKey="Coakley E">E Coakley</name></author><author><name sortKey="Petropoulos, C" uniqKey="Petropoulos C">C Petropoulos</name></author><author><name sortKey="Whitcomb, J" uniqKey="Whitcomb J">J Whitcomb</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS One</journal-id><journal-id journal-id-type="iso-abbrev">PLoS ONE</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosone</journal-id><journal-title-group><journal-title>PLoS ONE</journal-title></journal-title-group><issn pub-type="epub">1932-6203</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">23308267</article-id><article-id pub-id-type="pmc">3538727</article-id><article-id pub-id-type="publisher-id">PONE-D-12-09094</article-id><article-id pub-id-type="doi">10.1371/journal.pone.0053636</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Biochemistry</subject><subj-group><subject>Drug Discovery</subject></subj-group></subj-group><subj-group><subject>Biotechnology</subject><subj-group><subject>Drug Discovery</subject></subj-group></subj-group><subj-group><subject>Microbiology</subject><subj-group><subject>Virology</subject><subj-group><subject>Antivirals</subject></subj-group></subj-group></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Chemistry</subject><subj-group><subject>Medicinal Chemistry</subject></subj-group></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Medicine</subject><subj-group><subject>Drugs and Devices</subject><subj-group><subject>Drug Research and Development</subject><subj-group><subject>Drug Discovery</subject></subj-group></subj-group></subj-group><subj-group><subject>Infectious diseases</subject><subj-group><subject>Viral diseases</subject><subj-group><subject>HIV</subject><subj-group><subject>HIV diagnosis and management</subject></subj-group></subj-group></subj-group></subj-group><subj-group><subject>Obstetrics and Gynecology</subject><subj-group><subject>Genitourinary Infections</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group><subj-group><subject>Urology</subject><subj-group><subject>Genitourinary Infections</subject><subj-group><subject>HIV</subject></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>Design, Synthesis and Biological Evaluation of Novel Piperazine Derivatives as CCR5 Antagonists</article-title><alt-title alt-title-type="running-head">Piperazine Derivatives as CCR5 Antagonists</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Tao</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Weng</surname><given-names>Zhiyong</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>¤</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dong</surname><given-names>Xiaowu</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Chen</surname><given-names>Linjie</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ma</surname><given-names>Ling</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Cen</surname><given-names>Shan</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhou</surname><given-names>Naiming</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Hu</surname><given-names>Yongzhou</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Zhejiang University-École Normale Supérieure Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Institute of Biochemistry, College of Life Sciences, Zhejiang University, Hangzhou, China</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Insititute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, Beijing, China</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Peking Union Medical College, Beijing, China</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Wainberg</surname><given-names>Mark</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1"><addr-line>McGill University AIDS Centre, Canada</addr-line></aff><author-notes><corresp id="cor1">* E-mail: <email>Lt601@zju.edu.cn</email> (TL); <email>znm2000@yahoo.com</email> (NZ); <email>Huyz@zju.edu.cn</email> (YH)</corresp><fn fn-type="COI-statement"><p><bold>Competing Interests: </bold>The authors have declared that no competing interests exist.</p></fn><fn fn-type="con"><p>Conceived and designed the experiments: TL ZW YH NZ SC. Performed the experiments: ZW XD LC LM. Analyzed the data: TL ZW LC NZ SC. Contributed reagents/materials/analysis tools: XD LC NZ LM SC. Wrote the paper: TL ZW.</p></fn><fn id="fn1" fn-type="current-aff"><label>¤</label><p>Current address: Hangzhou No.2 High School of Zhejiang Province, Hangzhou, China</p></fn></author-notes><pub-date pub-type="collection"><year>2013</year></pub-date><pub-date pub-type="epub"><day>7</day><month>1</month><year>2013</year></pub-date><volume>8</volume><issue>1</issue><elocation-id>e53636</elocation-id><history><date date-type="received"><day>30</day><month>3</month><year>2012</year></date><date date-type="accepted"><day>3</day><month>12</month><year>2012</year></date></history><permissions><copyright-statement>© 2013 Liu et al</copyright-statement><copyright-year>2013</copyright-year><copyright-holder>Liu et al</copyright-holder><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p></license></permissions><abstract><p>By using a fragment-assembly strategy and bioisosteric-replacement principle, a series of novel piperazine derivatives were designed, synthesized, and evaluated for their cellular target-effector fusion activities and in vitro antiviral activities against HIV-1. Preliminary structure-activity relationships (SARs) of target compounds were concluded in this study, and five compounds were found to exhibited medium to potent CCR5 fusion activities with IC<sub>50</sub> values in low micromolar level. Among evaluated compounds, <bold>23 h</bold> was found to be a CCR5 antagonist with an IC<sub>50</sub> value of 6.29 µM and an anti-HIV-1 inhibitor with an IC<sub>50</sub> value of 0.44 µM.</p></abstract><funding-group><funding-statement>This study was supported by grants from the National Nature Science Foundation of China (number 81072515). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement></funding-group><counts><page-count count="5"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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