Back to Search
Start Over
Novel bifunctional quinolonyl diketo acid derivatives as HIV-1 integrase inhibitors: design, synthesis, biological activities, and mechanism of action.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2006 Mar 23; Vol. 49 (6), pp. 1939-45. - Publication Year :
- 2006
-
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.
- Subjects :
- Catalytic Domain
Cell Line
DNA, Viral chemistry
Drug Design
HIV Integrase chemistry
HIV Integrase Inhibitors chemistry
HIV Integrase Inhibitors pharmacology
Humans
Hydroxybutyrates chemistry
Hydroxybutyrates pharmacology
Keto Acids chemistry
Keto Acids pharmacology
Models, Molecular
Protein Binding
Protein Structure, Tertiary
Quinolones chemistry
Quinolones pharmacology
Structure-Activity Relationship
HIV Integrase metabolism
HIV Integrase Inhibitors chemical synthesis
HIV-1 drug effects
Hydroxybutyrates chemical synthesis
Keto Acids chemical synthesis
Quinolones chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0022-2623
- Volume :
- 49
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 16539381
- Full Text :
- https://doi.org/10.1021/jm0511583