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

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.

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► New compounds with hydrophilic or hydrophobic groups at C-6 were synthesized.
► Substitution at C-6 does not lead to a significant improvement of HIV-1 IN inhibition.
► A new IN/DNA model was build considering octahedral geometry of the two Mg2+ ions.
► Docking studies including explicit water molecules were performed.
► The binding mode obtained strongly corroborate with observed biological activities.