Synthesis, biological evaluation and molecular modeling studies of N-aryl-2-arylthioacetamides as non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of N-aryl-2-arylthioacetamide derivatives (2-4) designed as non-nucleoside reverse transcriptase inhibitors was synthesized and evaluated for their inhibitory activity against HIV-1 (IIIB) replication in MT-4 cell cultures. The compounds 2-4 were performed by the reaction of thiols and 2-chloro-N-substituted-acetamides and active in the lower micromolar concentration (1.25-20.83 μM). The studies of structure-activity relationship suggested that 1H-benzo[d]imidazole ring at arylthio moiety strongly improved the anti-HIV activity and consistent with the experimental data. The results of molecular modeling and docking within the RT non-nucleoside binding site using AutoDock confirmed that the 3 series, similar to other non-nucleoside reverse transcriptase inhibitors such as N-(5-chloro-2-pyridinyl)-N'-[2-(4-ethoxy-3-fluoro-2-pyridinyl)ethyl]-thiourea (PETT), was assumed in a butterfly-like conformation and helped to rationalize some SARs and the biological activity data.