Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41
On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A 1 , NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized....
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| Veröffentlicht in: | Journal of medicinal chemistry 2008-12, Vol.51 (24), p.7843-7854 |
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| container_title | Journal of medicinal chemistry |
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| creator | Liu, Kun Lu, Hong Hou, Ling Qi, Zhi Teixeira, Cátia Barbault, Florent Fan, Bo-Tao Liu, Shuwen Jiang, Shibo Xie, Lan |
| description | On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A 1 , NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure−activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A 12 ), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A 12 could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor. |
| doi_str_mv | 10.1021/jm800869t |
| format | Article |
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We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure−activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A 12 ), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A 12 could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm800869t</identifier><identifier>PMID: 19053778</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Columbus, OH: American Chemical Society</publisher><subject>Animals ; Anti-HIV Agents - chemistry ; Antibiotics. Antiinfectious agents. Antiparasitic agents ; Antiviral agents ; Antiviral Agents - chemistry ; Antiviral Agents - pharmacology ; Biological and medical sciences ; Chemistry, Pharmaceutical - methods ; Drug Design ; HIV Envelope Protein gp41 - chemistry ; HIV Fusion Inhibitors - chemistry ; HIV Fusion Inhibitors - pharmacology ; Humans ; Inhibitory Concentration 50 ; Medical sciences ; Models, Chemical ; Models, Molecular ; Molecular Conformation ; Pharmacology. Drug treatments ; Protein Structure, Secondary ; Pyrroles - chemistry ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2008-12, Vol.51 (24), p.7843-7854</ispartof><rights>Copyright © 2008 American Chemical Society</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a537t-91351e8aaee99bb8ee7b56fb65e3dda32625cbc0cb49d3498abf623a5436d3ca3</citedby><cites>FETCH-LOGICAL-a537t-91351e8aaee99bb8ee7b56fb65e3dda32625cbc0cb49d3498abf623a5436d3ca3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm800869t$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm800869t$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>230,314,776,780,881,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20985229$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19053778$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Kun</creatorcontrib><creatorcontrib>Lu, Hong</creatorcontrib><creatorcontrib>Hou, Ling</creatorcontrib><creatorcontrib>Qi, Zhi</creatorcontrib><creatorcontrib>Teixeira, Cátia</creatorcontrib><creatorcontrib>Barbault, Florent</creatorcontrib><creatorcontrib>Fan, Bo-Tao</creatorcontrib><creatorcontrib>Liu, Shuwen</creatorcontrib><creatorcontrib>Jiang, Shibo</creatorcontrib><creatorcontrib>Xie, Lan</creatorcontrib><title>Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A 1 , NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure−activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A 12 ), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A 12 could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.</description><subject>Animals</subject><subject>Anti-HIV Agents - chemistry</subject><subject>Antibiotics. Antiinfectious agents. Antiparasitic agents</subject><subject>Antiviral agents</subject><subject>Antiviral Agents - chemistry</subject><subject>Antiviral Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Chemistry, Pharmaceutical - methods</subject><subject>Drug Design</subject><subject>HIV Envelope Protein gp41 - chemistry</subject><subject>HIV Fusion Inhibitors - chemistry</subject><subject>HIV Fusion Inhibitors - pharmacology</subject><subject>Humans</subject><subject>Inhibitory Concentration 50</subject><subject>Medical sciences</subject><subject>Models, Chemical</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Protein Structure, Secondary</subject><subject>Pyrroles - chemistry</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkU9v1DAQxS0EokvhwBdAvnBAasB_Yie5IJVtS1eqoKgL4maNEyfrJWtHdnbVHPnmuNrVFiROHml-8_zmDUKvKXlPCaMf1puSkFJW4xM0o4KRLC9J_hTNCGEsY5LxE_QixjUhhFPGn6MTWhHBi6Kcod8XJtrOneG7yY2rVMczDK7Bn6zvfWdr6PHlDvotjNY77Fv8JZtD0P5-GlbGTf0wheB7gy9MsLsE7UzEEPGtH40b8fXiB77axofRhVtZbUcfIl5C6MxoXYe7Iacv0bMW-mheHd5T9P3qcjm_zm6-fl7Mz28ySFbHrKJcUFMCGFNVWpfGFFrIVktheNMAT2uKWtek1nnV8LwqQbdpcxA5lw2vgZ-ij3vdYas3pqmTvwC9GoLdQJiUB6v-7Ti7Up3fKSaFFAVNAu_2AnXwMQbTHmcpUQ93UMc7JPbN3589kofgE_D2AEBMIbcBXG3jkWOkKgVjVeKyPWfjaO6PfQi_lCx4IdTy9k7JXJY_Ofmmlo-6UEe19tvgUqb_MfgHFcCu7Q</recordid><startdate>20081225</startdate><enddate>20081225</enddate><creator>Liu, Kun</creator><creator>Lu, Hong</creator><creator>Hou, Ling</creator><creator>Qi, Zhi</creator><creator>Teixeira, Cátia</creator><creator>Barbault, Florent</creator><creator>Fan, Bo-Tao</creator><creator>Liu, Shuwen</creator><creator>Jiang, Shibo</creator><creator>Xie, Lan</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope></search><sort><creationdate>20081225</creationdate><title>Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41</title><author>Liu, Kun ; Lu, Hong ; Hou, Ling ; Qi, Zhi ; Teixeira, Cátia ; Barbault, Florent ; Fan, Bo-Tao ; Liu, Shuwen ; Jiang, Shibo ; Xie, Lan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a537t-91351e8aaee99bb8ee7b56fb65e3dda32625cbc0cb49d3498abf623a5436d3ca3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Anti-HIV Agents - chemistry</topic><topic>Antibiotics. Antiinfectious agents. Antiparasitic agents</topic><topic>Antiviral agents</topic><topic>Antiviral Agents - chemistry</topic><topic>Antiviral Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Chemistry, Pharmaceutical - methods</topic><topic>Drug Design</topic><topic>HIV Envelope Protein gp41 - chemistry</topic><topic>HIV Fusion Inhibitors - chemistry</topic><topic>HIV Fusion Inhibitors - pharmacology</topic><topic>Humans</topic><topic>Inhibitory Concentration 50</topic><topic>Medical sciences</topic><topic>Models, Chemical</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Pharmacology. Drug treatments</topic><topic>Protein Structure, Secondary</topic><topic>Pyrroles - chemistry</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Kun</creatorcontrib><creatorcontrib>Lu, Hong</creatorcontrib><creatorcontrib>Hou, Ling</creatorcontrib><creatorcontrib>Qi, Zhi</creatorcontrib><creatorcontrib>Teixeira, Cátia</creatorcontrib><creatorcontrib>Barbault, Florent</creatorcontrib><creatorcontrib>Fan, Bo-Tao</creatorcontrib><creatorcontrib>Liu, Shuwen</creatorcontrib><creatorcontrib>Jiang, Shibo</creatorcontrib><creatorcontrib>Xie, Lan</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Kun</au><au>Lu, Hong</au><au>Hou, Ling</au><au>Qi, Zhi</au><au>Teixeira, Cátia</au><au>Barbault, Florent</au><au>Fan, Bo-Tao</au><au>Liu, Shuwen</au><au>Jiang, Shibo</au><au>Xie, Lan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-12-25</date><risdate>2008</risdate><volume>51</volume><issue>24</issue><spage>7843</spage><epage>7854</epage><pages>7843-7854</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>On the basis of the structures of small-molecule hits targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole (2, NB-2), and N-(3-carboxy-4-chloro)phenylpyrrole (A 1 , NB-64), 42 N-carboxyphenylpyrrole derivatives in two categories (A and B series) were designed and synthesized. We found that 11 compounds exhibited promising anti-HIV-1 activity at micromolar level and their antiviral activity was correlated with their inhibitory activity on gp41 six-helix bundle formation, suggesting that these compounds block HIV fusion and entry by disrupting gp41 core formation. The structure−activity relationship and molecular docking analysis revealed that the carboxyl group could interact with either Arg579 or Lys574 to form salt bridges and two methyl groups on the pyrrole ring were favorable for interaction with the residues in gp41 pocket. The most active compound, N-(3-carboxy-4-hydroxy)phenyl-2,5-dimethylpyrrole (A 12 ), partially occupied the deep hydrophobic pocket, suggesting that enlarging the molecular size of A 12 could improve its binding affinity and anti-HIV-1 activity for further development as a small-molecule HIV fusion and entry inhibitor.</abstract><cop>Columbus, OH</cop><pub>American Chemical Society</pub><pmid>19053778</pmid><doi>10.1021/jm800869t</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2008-12, Vol.51 (24), p.7843-7854 |
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| subjects | Animals Anti-HIV Agents - chemistry Antibiotics. Antiinfectious agents. Antiparasitic agents Antiviral agents Antiviral Agents - chemistry Antiviral Agents - pharmacology Biological and medical sciences Chemistry, Pharmaceutical - methods Drug Design HIV Envelope Protein gp41 - chemistry HIV Fusion Inhibitors - chemistry HIV Fusion Inhibitors - pharmacology Humans Inhibitory Concentration 50 Medical sciences Models, Chemical Models, Molecular Molecular Conformation Pharmacology. Drug treatments Protein Structure, Secondary Pyrroles - chemistry Structure-Activity Relationship |
| title | Design, Synthesis, and Biological Evaluation of N-Carboxyphenylpyrrole Derivatives as Potent HIV Fusion Inhibitors Targeting gp41 |
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