非核苷类HIV-1逆转录酶抑制剂——二芳烃取代苯并咪唑类衍生物的设计、合成和活性评价

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

为寻找新型抗HIV-1非核苷类逆转录酶抑制剂先导物,靶向设计、合成和评价了苯并咪唑类系列化合物的抗HIV活性。在27个目标化合物中发现了3个苯并咪唑类化合物(A6、B3、B6)具有良好的抗HIV活性,EC50值分别为15.33、9.81和1.37μmol·L?1;并获知该系列化合物的初步构效关系。抗HIV的二芳烃取代苯并咪唑类活性化合物,可作为进一步结构优化、发现高活性新结构抗HIV新先导物的新起点。

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.