Synthesis, biological evaluation and molecular modeling studies of quinolonyl diketo acid derivatives: New structural insight into the HIV-1 integrase inhibition

• DOI: 10.1016/j.ejmech.2011.02.028
• Publication Date: 2011-02-23T09:52:26Z
• Authors: Pierre Vandurm; Allan Guiguen; Christine Cauvin; Benoît Georges; Kiet Le Van; Catherine Michaux; Christelle Cardona; Gladys Mbemba; Jean-François Mou...; László Hevesi; Carine Van Lint; Johan Wouters
• Keywords: Quinolones -- chemical synthesis -- chemistry -- pharmacology; Models, Molecular; Anti-HIV Agents; HIV Integrase -- chemistry -- metabolism; Molecular modeling; HIV Integrase; Anti-HIV Agents -- chemical synthesis -- chemistry -- pharmacology; Quinolones; Docking; Dose-Response Relationship; Structure-Activity Relationship; 03 medical and health sciences; Models; Catalytic Domain; Anti-integrase activity; HIV Integrase Inhibitors; Antiviral activity; Quinolonyl diketo acid; 0303 health sciences; Dose-Response Relationship, Drug; Molecular Structure; HIV -- drug effects; Molecular; HIV; Stereoisomerism; Sciences bio-médicales et agricoles; HIV-1 IN; Keto Acids; 3. Good health; Drug Design; Catalytic Domain -- drug effects; Drug; HIV Integrase Inhibitors -- chemical synthesis -- chemistry -- pharmacology; Keto Acids -- chemical synthesis -- chemistry -- pharmacology

New quinolonyl diketo acid compounds bearing various substituents at position 6 of the quinolone scaffold were designed and synthesized as potential HIV-1 integrase inhibitors. These new compounds were evaluated for their antiviral and anti-integrase activity and showed inhibitory potency similar to that of 6-bromide analog 2. Molecular modeling and docking studies were performed to rationalize these data and to provide a detailed understanding of the mechanism of inhibition for this class of compounds.