2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors
The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg...
Gespeichert in:
| Veröffentlicht in: | Journal of medicinal chemistry 2008-01, Vol.51 (2), p.251-259 |
|---|---|
| Hauptverfasser: | , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 259 |
|---|---|
| container_issue | 2 |
| container_start_page | 251 |
| container_title | Journal of medicinal chemistry |
| container_volume | 51 |
| creator | Zhao, Xue Zhi Semenova, Elena A Vu, B. Christie Maddali, Kasthuraiah Marchand, Christophe Hughes, Stephen H Pommier, Yves Burke, Terrence R |
| description | The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3′-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors. |
| doi_str_mv | 10.1021/jm070715d |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_70206700</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>70206700</sourcerecordid><originalsourceid>FETCH-LOGICAL-a351t-a8ad60aab7ff76c4e61c2bb9ae9be6d4ff3a42a1bd98c7e1834a91f8599909093</originalsourceid><addsrcrecordid>eNptkF9LwzAUxYMobk4f_AKyFwVh0ZukTdpHnboO5h_Y9DWkTeo612YmHWzf3krHfJH7cA_3_jiXexA6J3BDgJLbRQkCBAn1AeqSkAIOIggOUReAUkw5ZR104v0CABih7Bh1SARxyAPWRRM6YPihmG-1s5gPBNat3mwxSXDhbVFpu8QE28rge-WN7ifjD0z646o2n64ZNGpepEVtnT9FR7laenO26z30_vQ4GyZ48joaD-8mWLGQ1FhFSnNQKhV5LngWGE4ymqaxMnFquA7ynKmAKpLqOMqEIRELVEzyKIzjGJpiPXTV-q6c_V4bX8uy8JlZLlVl7NpLARS4aL7toesWzJz13plcrlxRKreVBORvdHIfXcNe7EzXaWn0H7nLqgFwCxS-Npv9XrkvyQUToZy9TeUo4eHsGV7ktOEvW15lXi7s2lVNJv8c_gEur4IW</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>70206700</pqid></control><display><type>article</type><title>2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors</title><source>MEDLINE</source><source>American Chemical Society Journals</source><creator>Zhao, Xue Zhi ; Semenova, Elena A ; Vu, B. Christie ; Maddali, Kasthuraiah ; Marchand, Christophe ; Hughes, Stephen H ; Pommier, Yves ; Burke, Terrence R</creator><creatorcontrib>Zhao, Xue Zhi ; Semenova, Elena A ; Vu, B. Christie ; Maddali, Kasthuraiah ; Marchand, Christophe ; Hughes, Stephen H ; Pommier, Yves ; Burke, Terrence R</creatorcontrib><description>The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3′-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm070715d</identifier><identifier>PMID: 18095643</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Benzamides - chemical synthesis ; Benzamides - chemistry ; Benzamides - pharmacology ; Catalysis ; Cations, Divalent ; Cell Line ; Cell Line, Tumor ; Genetic Vectors ; HIV Integrase Inhibitors - chemical synthesis ; HIV Integrase Inhibitors - chemistry ; HIV Integrase Inhibitors - pharmacology ; HIV-1 - drug effects ; HIV-1 - genetics ; Humans ; Hydrazines - chemical synthesis ; Hydrazines - chemistry ; Hydrazines - pharmacology ; Isoindoles - chemical synthesis ; Isoindoles - chemistry ; Isoindoles - pharmacology ; Magnesium - metabolism ; Molecular Conformation ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2008-01, Vol.51 (2), p.251-259</ispartof><rights>Copyright © 2008 U.S. Government</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a351t-a8ad60aab7ff76c4e61c2bb9ae9be6d4ff3a42a1bd98c7e1834a91f8599909093</citedby><cites>FETCH-LOGICAL-a351t-a8ad60aab7ff76c4e61c2bb9ae9be6d4ff3a42a1bd98c7e1834a91f8599909093</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/jm070715d$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm070715d$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18095643$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhao, Xue Zhi</creatorcontrib><creatorcontrib>Semenova, Elena A</creatorcontrib><creatorcontrib>Vu, B. Christie</creatorcontrib><creatorcontrib>Maddali, Kasthuraiah</creatorcontrib><creatorcontrib>Marchand, Christophe</creatorcontrib><creatorcontrib>Hughes, Stephen H</creatorcontrib><creatorcontrib>Pommier, Yves</creatorcontrib><creatorcontrib>Burke, Terrence R</creatorcontrib><title>2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3′-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.</description><subject>Benzamides - chemical synthesis</subject><subject>Benzamides - chemistry</subject><subject>Benzamides - pharmacology</subject><subject>Catalysis</subject><subject>Cations, Divalent</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Genetic Vectors</subject><subject>HIV Integrase Inhibitors - chemical synthesis</subject><subject>HIV Integrase Inhibitors - chemistry</subject><subject>HIV Integrase Inhibitors - pharmacology</subject><subject>HIV-1 - drug effects</subject><subject>HIV-1 - genetics</subject><subject>Humans</subject><subject>Hydrazines - chemical synthesis</subject><subject>Hydrazines - chemistry</subject><subject>Hydrazines - pharmacology</subject><subject>Isoindoles - chemical synthesis</subject><subject>Isoindoles - chemistry</subject><subject>Isoindoles - pharmacology</subject><subject>Magnesium - metabolism</subject><subject>Molecular Conformation</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>eNptkF9LwzAUxYMobk4f_AKyFwVh0ZukTdpHnboO5h_Y9DWkTeo612YmHWzf3krHfJH7cA_3_jiXexA6J3BDgJLbRQkCBAn1AeqSkAIOIggOUReAUkw5ZR104v0CABih7Bh1SARxyAPWRRM6YPihmG-1s5gPBNat3mwxSXDhbVFpu8QE28rge-WN7ifjD0z646o2n64ZNGpepEVtnT9FR7laenO26z30_vQ4GyZ48joaD-8mWLGQ1FhFSnNQKhV5LngWGE4ymqaxMnFquA7ynKmAKpLqOMqEIRELVEzyKIzjGJpiPXTV-q6c_V4bX8uy8JlZLlVl7NpLARS4aL7toesWzJz13plcrlxRKreVBORvdHIfXcNe7EzXaWn0H7nLqgFwCxS-Npv9XrkvyQUToZy9TeUo4eHsGV7ktOEvW15lXi7s2lVNJv8c_gEur4IW</recordid><startdate>20080124</startdate><enddate>20080124</enddate><creator>Zhao, Xue Zhi</creator><creator>Semenova, Elena A</creator><creator>Vu, B. Christie</creator><creator>Maddali, Kasthuraiah</creator><creator>Marchand, Christophe</creator><creator>Hughes, Stephen H</creator><creator>Pommier, Yves</creator><creator>Burke, Terrence R</creator><general>American Chemical Society</general><scope>BSCLL</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>7X8</scope></search><sort><creationdate>20080124</creationdate><title>2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors</title><author>Zhao, Xue Zhi ; Semenova, Elena A ; Vu, B. Christie ; Maddali, Kasthuraiah ; Marchand, Christophe ; Hughes, Stephen H ; Pommier, Yves ; Burke, Terrence R</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a351t-a8ad60aab7ff76c4e61c2bb9ae9be6d4ff3a42a1bd98c7e1834a91f8599909093</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Benzamides - chemical synthesis</topic><topic>Benzamides - chemistry</topic><topic>Benzamides - pharmacology</topic><topic>Catalysis</topic><topic>Cations, Divalent</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Genetic Vectors</topic><topic>HIV Integrase Inhibitors - chemical synthesis</topic><topic>HIV Integrase Inhibitors - chemistry</topic><topic>HIV Integrase Inhibitors - pharmacology</topic><topic>HIV-1 - drug effects</topic><topic>HIV-1 - genetics</topic><topic>Humans</topic><topic>Hydrazines - chemical synthesis</topic><topic>Hydrazines - chemistry</topic><topic>Hydrazines - pharmacology</topic><topic>Isoindoles - chemical synthesis</topic><topic>Isoindoles - chemistry</topic><topic>Isoindoles - pharmacology</topic><topic>Magnesium - metabolism</topic><topic>Molecular Conformation</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zhao, Xue Zhi</creatorcontrib><creatorcontrib>Semenova, Elena A</creatorcontrib><creatorcontrib>Vu, B. Christie</creatorcontrib><creatorcontrib>Maddali, Kasthuraiah</creatorcontrib><creatorcontrib>Marchand, Christophe</creatorcontrib><creatorcontrib>Hughes, Stephen H</creatorcontrib><creatorcontrib>Pommier, Yves</creatorcontrib><creatorcontrib>Burke, Terrence R</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhao, Xue Zhi</au><au>Semenova, Elena A</au><au>Vu, B. Christie</au><au>Maddali, Kasthuraiah</au><au>Marchand, Christophe</au><au>Hughes, Stephen H</au><au>Pommier, Yves</au><au>Burke, Terrence R</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2008-01-24</date><risdate>2008</risdate><volume>51</volume><issue>2</issue><spage>251</spage><epage>259</epage><pages>251-259</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>The bis-salicylhydrazides class of HIV-1 integrase (IN) inhibitors has been postulated to function by metal chelation. However, members of this series exhibit potent inhibition only when Mn2+ is used as cofactor. The current study found that bis-aroylhydrazides could acquire inhibitory potency in Mg2+ using dihydroxybenzoyl substituents as both the right and left components of the hydrazide moiety. Employing a 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one ring system as a conformationally constrained 2,3-dihydroxybenzoyl equivalent provided good selectivity for IN-catalyzed strand transfer versus the 3′-processing reactions as well as antiviral efficacy in cells using HIV-1 based vectors.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>18095643</pmid><doi>10.1021/jm070715d</doi><tpages>9</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2008-01, Vol.51 (2), p.251-259 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_70206700 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Benzamides - chemical synthesis Benzamides - chemistry Benzamides - pharmacology Catalysis Cations, Divalent Cell Line Cell Line, Tumor Genetic Vectors HIV Integrase Inhibitors - chemical synthesis HIV Integrase Inhibitors - chemistry HIV Integrase Inhibitors - pharmacology HIV-1 - drug effects HIV-1 - genetics Humans Hydrazines - chemical synthesis Hydrazines - chemistry Hydrazines - pharmacology Isoindoles - chemical synthesis Isoindoles - chemistry Isoindoles - pharmacology Magnesium - metabolism Molecular Conformation Structure-Activity Relationship |
| title | 2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based HIV-1 Integrase Inhibitors |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-29T17%3A50%3A10IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=2,3-Dihydro-6,7-dihydroxy-1H-isoindol-1-one-Based%20HIV-1%20Integrase%20Inhibitors&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Zhao,%20Xue%20Zhi&rft.date=2008-01-24&rft.volume=51&rft.issue=2&rft.spage=251&rft.epage=259&rft.pages=251-259&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm070715d&rft_dat=%3Cproquest_cross%3E70206700%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=70206700&rft_id=info:pmid/18095643&rfr_iscdi=true |