SrasV1, PubMed, Checkpoint, bibRecord, 002087

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.

Identifieur interne : 002087 ( PubMed/Checkpoint ); précédent : 002086; suivant : 002088

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.

Auteurs : Roberto Di Santo [Italie] ; Roberta Costi ; Alessandra Roux ; Marino Artico ; Antonio Lavecchia ; Luciana Marinelli ; Ettore Novellino ; Lucia Palmisano ; Mauro Andreotti ; Roberta Amici ; Clementina Maria Galluzzo ; Lucia Nencioni ; Anna Teresa Palamara ; Yves Pommier ; Christophe Marchand

Source :

Journal of medicinal chemistry [ 0022-2623 ] ; 2006.

RBID : pubmed:16539381

Descripteurs français

English descriptors

KwdEn :
- Catalytic Domain, Cell Line, DNA, Viral (chemistry), Drug Design, HIV Integrase (chemistry), HIV Integrase (metabolism), HIV Integrase Inhibitors (chemical synthesis), HIV Integrase Inhibitors (chemistry), HIV Integrase Inhibitors (pharmacology), HIV-1 (drug effects), Humans, Hydroxybutyrates (chemical synthesis), Hydroxybutyrates (chemistry), Hydroxybutyrates (pharmacology), Keto Acids (chemical synthesis), Keto Acids (chemistry), Keto Acids (pharmacology), Models, Molecular, Protein Binding, Protein Structure, Tertiary, Quinolones (chemical synthesis), Quinolones (chemistry), Quinolones (pharmacology), Structure-Activity Relationship.
MESH :
- chemical , chemical synthesis : HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- chemical , chemistry : DNA, Viral, HIV Integrase, HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- chemical , metabolism : HIV Integrase.
- chemical , pharmacology : HIV Integrase Inhibitors, Hydroxybutyrates, Keto Acids, Quinolones.
- drug effects : HIV-1.
- Catalytic Domain, Cell Line, Drug Design, Humans, Models, Molecular, Protein Binding, Protein Structure, Tertiary, Structure-Activity Relationship.

Abstract

The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.

DOI: 10.1021/jm0511583
PubMed: 16539381

Affiliations:

Italie

Links toward previous steps (curation, corpus...)

to stream PubMed, to step Corpus: 002309
to stream PubMed, to step Curation: 002309

Links to Exploration step

pubmed:16539381

Le document en format XML

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<term>HIV Integrase (metabolism)</term>
<term>HIV Integrase Inhibitors (chemical synthesis)</term>
<term>HIV Integrase Inhibitors (chemistry)</term>
<term>HIV Integrase Inhibitors (pharmacology)</term>
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<term>Cétoacides (synthèse chimique)</term>
<term>Domaine catalytique</term>
<term>Humains</term>
<term>Hydroxy-butyrates ()</term>
<term>Hydroxy-butyrates (pharmacologie)</term>
<term>Hydroxy-butyrates (synthèse chimique)</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>Modèles moléculaires</term>
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<term>Cell Line</term>
<term>Drug Design</term>
<term>Humans</term>
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<term>Protein Binding</term>
<term>Protein Structure, Tertiary</term>
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<front><div type="abstract" xml:lang="en">The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.</div>
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<Abstract><AbstractText>The virally encoded integrase protein is an essential enzyme in the life cycle of the HIV-1 virus and represents an attractive and validated target in the development of therapeutics against HIV infection. Drugs that selectively inhibit this enzyme, when used in combination with inhibitors of reverse transcriptase and protease, are believed to be highly effective in suppressing the viral replication. Among the HIV-1 integrase inhibitors, the beta-diketo acids (DKAs) represent a major lead for anti-HIV-1 drug development. In this study, novel bifunctional quinolonyl diketo acid derivatives were designed, synthesized, and tested for their inhibitory ability against HIV-1 integrase. The compounds are potent inhibitors of integrase activity. Particularly, derivative 8 is a potent IN inhibitor for both steps of the reaction (3'-processing and strand transfer) and exhibits both high antiviral activity against HIV-1 infected cells and low cytotoxicity. Molecular modeling studies provide a plausible mechanism of action, which is consistent with ligand SARs and enzyme photo-cross-linking experiments.</AbstractText>
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Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.

Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.

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