HIV Research Today is a free monthly online journal that collates and summarizes the latest research about HIV, including details on human immunodeficiency virus, testing, treatment, prevention, vaccines, aids.

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

Di Santo R, Costi R, Roux A, Artico M, Lavecchia A, Marinelli L, Novellino E, Palmisano L, Andreotti M, Amici R, Galluzzo CM, Nencioni L, Palamara AT, Pommier Y, Marchand C

Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, and Istituto di Microbiologia, Università di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy. roberto.disanto@uniroma1.it

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.

Published 16 March 2006 in J Med Chem, 49(6): 1939-45.
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