SrasV1, France, Analysis, bibRecord, 000406

Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture

Identifieur interne : 000406 ( France/Analysis ); précédent : 000405; suivant : 000407

Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture

Auteurs : F. Zouhiri [France] ; J.-F. Mouscadet [France] ; K. Mekouar [France] ; D. Desmaële [France] ; D. Savoure [France] ; H. Leh [France] ; F. Subra [France] ; M. Le Bret [France] ; C. Auclair [France] ; J. D'Angelo [France]

Source :

Journal of medicinal chemistry : (Print) [ 0022-2623 ] ; 2000.

RBID : Pascal:00-0280537

Descripteurs français

KwdFr :
- Agents antiVIH (), Agents antiVIH (pharmacologie), Agents antiVIH (synthèse chimique), Domaine catalytique, Humains, Inhibiteurs de l'intégrase du VIH (), Inhibiteurs de l'intégrase du VIH (pharmacologie), Inhibiteurs de l'intégrase du VIH (synthèse chimique), Intégrase du VIH (), Intégrase du VIH (métabolisme), Liaison aux protéines, Lignée cellulaire, Quinoléines (), Quinoléines (pharmacologie), Quinoléines (synthèse chimique), Relation structure-activité, Réplication virale, Styrènes (), Styrènes (pharmacologie), Styrènes (synthèse chimique), VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ().
MESH :
- métabolisme : Intégrase du VIH.
- pharmacologie : Agents antiVIH, Inhibiteurs de l'intégrase du VIH, Quinoléines, Styrènes.
- synthèse chimique : Agents antiVIH, Inhibiteurs de l'intégrase du VIH, Quinoléines, Styrènes.
Pascal (Inist)
- Agents antiVIH, Domaine catalytique, Humains, Inhibiteurs de l'intégrase du VIH, Intégrase du VIH, Liaison aux protéines, Lignée cellulaire, Quinoléines, Relation structure activité, Relation structure-activité, Réplication virale, Styrènes, Synthèse chimique, Hétérocycle azote, Composé bicyclique, Composé aromatique, Phénols, Benzène dérivé, Styrène dérivé, Inhibiteur enzyme, Enzyme, Inhibition, Cycle développement virus, In vitro, Antiviral, VIH-1 (Virus de l'Immunodéficience Humaine de type 1), Virus HIV1, Mode liaison, Quinoléine-7-carboxylique acide(2-[2-arylvinyl]-8-hydroxy), Integrase.
Wicri :
- topic : Enzyme.

English descriptors

KwdEn :
- Anti-HIV Agents (chemical synthesis), Anti-HIV Agents (chemistry), Anti-HIV Agents (pharmacology), Antiviral, Aromatic compound, Benzene derivatives, Bicyclic compound, Binding mode, Catalytic Domain, Cell Line, Chemical synthesis, Enzyme, Enzyme inhibitor, HIV Integrase (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (chemistry), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), HIV-1 virus, Humans, In vitro, Inhibition, Nitrogen heterocycle, Phenols, Protein Binding, Quinolines (chemical synthesis), Quinolines (chemistry), Quinolines (pharmacology), Structure activity relation, Structure-Activity Relationship, Styrene derivatives, Styrenes (chemical synthesis), Styrenes (chemistry), Styrenes (pharmacology), Virus Replication, Virus replication cycle.
MESH :
- chemical , chemical synthesis : Anti-HIV Agents, HIV Integrase Inhibitors, Quinolines, Styrenes.
- chemical , chemistry : Anti-HIV Agents, HIV Integrase, HIV Integrase Inhibitors, Quinolines, Styrenes.
- chemical , metabolism : HIV Integrase.
- chemical , pharmacology : Anti-HIV Agents, HIV Integrase Inhibitors, Quinolines, Styrenes.
- drug effects : HIV-1.
- Catalytic Domain, Cell Line, Humans, Protein Binding, Structure-Activity Relationship, Virus Replication.

Abstract

Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.

Affiliations:

Links to Exploration step

Pascal:00-0280537

Le document en format XML

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<series><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
<imprint><date when="2000">2000</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
<seriesStmt><title level="j" type="main">Journal of medicinal chemistry : (Print)</title>
<title level="j" type="abbreviated">J. med. chem. : (Print)</title>
<idno type="ISSN">0022-2623</idno>
</seriesStmt>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Anti-HIV Agents (chemical synthesis)</term>
<term>Anti-HIV Agents (chemistry)</term>
<term>Anti-HIV Agents (pharmacology)</term>
<term>Antiviral</term>
<term>Aromatic compound</term>
<term>Benzene derivatives</term>
<term>Bicyclic compound</term>
<term>Binding mode</term>
<term>Catalytic Domain</term>
<term>Cell Line</term>
<term>Chemical synthesis</term>
<term>Enzyme</term>
<term>Enzyme inhibitor</term>
<term>HIV Integrase (chemistry)</term>
<term>HIV Integrase (metabolism)</term>
<term>HIV Integrase Inhibitors (chemical synthesis)</term>
<term>HIV Integrase Inhibitors (chemistry)</term>
<term>HIV Integrase Inhibitors (pharmacology)</term>
<term>HIV-1 (drug effects)</term>
<term>HIV-1 virus</term>
<term>Humans</term>
<term>In vitro</term>
<term>Inhibition</term>
<term>Nitrogen heterocycle</term>
<term>Phenols</term>
<term>Protein Binding</term>
<term>Quinolines (chemical synthesis)</term>
<term>Quinolines (chemistry)</term>
<term>Quinolines (pharmacology)</term>
<term>Structure activity relation</term>
<term>Structure-Activity Relationship</term>
<term>Styrene derivatives</term>
<term>Styrenes (chemical synthesis)</term>
<term>Styrenes (chemistry)</term>
<term>Styrenes (pharmacology)</term>
<term>Virus Replication</term>
<term>Virus replication cycle</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Agents antiVIH ()</term>
<term>Agents antiVIH (pharmacologie)</term>
<term>Agents antiVIH (synthèse chimique)</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Inhibiteurs de l'intégrase du VIH ()</term>
<term>Inhibiteurs de l'intégrase du VIH (pharmacologie)</term>
<term>Inhibiteurs de l'intégrase du VIH (synthèse chimique)</term>
<term>Intégrase du VIH ()</term>
<term>Intégrase du VIH (métabolisme)</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire</term>
<term>Quinoléines ()</term>
<term>Quinoléines (pharmacologie)</term>
<term>Quinoléines (synthèse chimique)</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Styrènes ()</term>
<term>Styrènes (pharmacologie)</term>
<term>Styrènes (synthèse chimique)</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1) ()</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemical synthesis" xml:lang="en"><term>Anti-HIV Agents</term>
<term>HIV Integrase Inhibitors</term>
<term>Quinolines</term>
<term>Styrenes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Anti-HIV Agents</term>
<term>HIV Integrase</term>
<term>HIV Integrase Inhibitors</term>
<term>Quinolines</term>
<term>Styrenes</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>HIV Integrase</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Anti-HIV Agents</term>
<term>HIV Integrase Inhibitors</term>
<term>Quinolines</term>
<term>Styrenes</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>HIV-1</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Intégrase du VIH</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Agents antiVIH</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Quinoléines</term>
<term>Styrènes</term>
</keywords>
<keywords scheme="MESH" qualifier="synthèse chimique" xml:lang="fr"><term>Agents antiVIH</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Quinoléines</term>
<term>Styrènes</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Catalytic Domain</term>
<term>Cell Line</term>
<term>Humans</term>
<term>Protein Binding</term>
<term>Structure-Activity Relationship</term>
<term>Virus Replication</term>
</keywords>
<keywords scheme="Pascal" xml:lang="fr"><term>Agents antiVIH</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Inhibiteurs de l'intégrase du VIH</term>
<term>Intégrase du VIH</term>
<term>Liaison aux protéines</term>
<term>Lignée cellulaire</term>
<term>Quinoléines</term>
<term>Relation structure activité</term>
<term>Relation structure-activité</term>
<term>Réplication virale</term>
<term>Styrènes</term>
<term>Synthèse chimique</term>
<term>Hétérocycle azote</term>
<term>Composé bicyclique</term>
<term>Composé aromatique</term>
<term>Phénols</term>
<term>Benzène dérivé</term>
<term>Styrène dérivé</term>
<term>Inhibiteur enzyme</term>
<term>Enzyme</term>
<term>Inhibition</term>
<term>Cycle développement virus</term>
<term>In vitro</term>
<term>Antiviral</term>
<term>VIH-1 (Virus de l'Immunodéficience Humaine de type 1)</term>
<term>Virus HIV1</term>
<term>Mode liaison</term>
<term>Quinoléine-7-carboxylique acide(2-[2-arylvinyl]-8-hydroxy)</term>
<term>Integrase</term>
</keywords>
<keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Enzyme</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en">Our prior studies showed that polyhydroxylated styrylquinolines are potent HIV-1 integrase (IN) inhibitors that block the replication of HIV-1 in cell culture at nontoxic concentrations. To explore the mechanism of action of these inhibitors, various novel styrylquinoline derivatives were synthesized and tested against HIV-1 IN and in cell-based assays. Regarding the in vitro experiments, the structural requirements for biological activity are a carboxyl group at C-7, a hydroxyl group at C-8 in the quinoline subunit, and an ancillary phenyl ring. However the in vitro inhibitory profile tolerates deep alterations of this ring, e.g. by the introduction of various substituents or its replacement by heteroatomic nuclei. Regarding the ex vivo assays, the structural requirements for activity are more stringent than for in vitro inhibition. Thus, in addition to an o-hydroxy acid group in the quinoline, the presence of one ortho pair of substituents at C-3' and C-4', particularly two hydroxyl groups, in the ancillary phenyl ring is imperatively required for inhibitory potency. Starting from literature data and the SARs developed in this work, a putative binding mode of styrylquinoline inhibitors to HIV-1 IN was derived.</div>
</front>
</TEI>
<affiliations><list><country><li>France</li>
</country>
<region><li>Île-de-France</li>
</region>
<settlement><li>Cachan</li>
<li>Châtenay-Malabry</li>
<li>Villejuif</li>
</settlement>
<orgName><li>Université Paris-Sud</li>
</orgName>
</list>
<tree><country name="France"><region name="Île-de-France"><name sortKey="Zouhiri, F" sort="Zouhiri, F" uniqKey="Zouhiri F" first="F." last="Zouhiri">F. Zouhiri</name>
</region>
<name sortKey="Auclair, C" sort="Auclair, C" uniqKey="Auclair C" first="C." last="Auclair">C. Auclair</name>
<name sortKey="D Angelo, J" sort="D Angelo, J" uniqKey="D Angelo J" first="J." last="D'Angelo">J. D'Angelo</name>
<name sortKey="Desmaele, D" sort="Desmaele, D" uniqKey="Desmaele D" first="D." last="Desmaële">D. Desmaële</name>
<name sortKey="Le Bret, M" sort="Le Bret, M" uniqKey="Le Bret M" first="M." last="Le Bret">M. Le Bret</name>
<name sortKey="Leh, H" sort="Leh, H" uniqKey="Leh H" first="H." last="Leh">H. Leh</name>
<name sortKey="Mekouar, K" sort="Mekouar, K" uniqKey="Mekouar K" first="K." last="Mekouar">K. Mekouar</name>
<name sortKey="Mouscadet, J F" sort="Mouscadet, J F" uniqKey="Mouscadet J" first="J.-F." last="Mouscadet">J.-F. Mouscadet</name>
<name sortKey="Savoure, D" sort="Savoure, D" uniqKey="Savoure D" first="D." last="Savoure">D. Savoure</name>
<name sortKey="Subra, F" sort="Subra, F" uniqKey="Subra F" first="F." last="Subra">F. Subra</name>
</country>
</tree>
</affiliations>
</record>

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Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture

Structure-activity relationships and binding mode of styrylquinolines as potent inhibitors of HIV-1 integrase and replication of HIV-1 in cell culture

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