Molecular modeling, synthesis and biological evaluation of N-heteroaryl compounds as reverse transcriptase inhibitors...

Different N-heteroaryl compounds bearing pyrimidine and benzimidazole moieties have been designed in silico using Discovery studio 2.5 software, synthesized and evaluated for their inhibitory activity as reverse transcriptase inhibitors against HIV-1 replication using laboratory adapted strains HIV-1IIIB (X4, subtype B) and HIV-1Ada5 (R5, subtype B), and the primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C). Cell-based assay showed that compounds were active at 1.394 μm concentrations (Selectivity Index: 1.29-38.39). The studies on structure-activity relationship clearly suggested anti-HIV activity of pyrimidine and benzimidazole derivatives and these findings were consistent with the in vitro cell-based experimental data. The results of molecular modeling and docking confirmed that all compounds assumed a butterfly-like conformation and showed H-bond, 'π-π' and 'π-+' and hydrophobic interactions within flexible non-nucleoside inhibitor binding pocket of HIV-1 reverse transcriptase, similar to known non-nucleoside reverse transcriptase inhibitors, such as nevirapine. In view of the results obtained, it can be said that the chemical skeletons of N, N'-bis-(pyridin-2-yl)-succinamide (14 and 15) and 1, 4-bis-benzoimidazol-1-yl-butane-1, 4-dione (16 and 17) may be used for developing potent inhibitors of HIV-1 replication, with suitable structure/pharmacophore modifications.