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Novel Bifunctional Quinolonyl Diketo Acid Derivatives as HIV-1 Integrase Inhibitors: Design, Synthesis, Biological Activities, and Mechanism of Action

2006; American Chemical Society; Volume: 49; Issue: 6 Linguagem: Inglês

10.1021/jm0511583

1520-4804

Roberto Di Santo, 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,

Click Chemistry and Applications

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.