Design, synthesis and biologic evaluation of diarylbenzimidazole derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors

Twenty seven new diarylbenzimidazole derivatives (A1−A21, B1−B6) were designed, synthesized, and evaluated in MT-2 cell line as potential HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) agents with a new skeleton based on molecular modeling technique and hit 1,2-diarylbenzimidazole A1 (EC₅₀ 69.9 μmol·L⁻¹).  Hence, 1,2-diarylbenzimidazoles A6 and B3, and 1,6-diarylbenzimidazole B6 showed obvious potency against HIV-1 replication in MT-2 cell line with EC₅₀ values of 15.33, 9.81 and 1.37 μmol·L⁻¹       respectively.  All target compounds were synthesized commonly from substituted 2-nitroanilines by 1−3 steps under mild reaction conditions.  Current studies provided preliminary SAR, thus indicating that 1,6-diaryl  substitution on the benzimidazole ring would be a right direction for further modification.  Furthermore, the docking studies demonstrated that B6 could fit well into the HIV-1 NNRTI binding pocket with a similar binding orientation and conformation to that of TMC278, a promising NNRTI candidate in clinical trial III, Therefore, active compound B6 could serve as a new starting point to develop a series of 1,6-diarylbenzimidazole derivatives as HIV-1 NNRTI agents with a novel skeleton.