title: [Design, synthesis and biologic evaluation of diarylbenzimidazole derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors].
abstract: 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 miromol x 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 micromol x 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 inclinical 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.
authors.affiliation: Institute ofPharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
authors.forename: Bing-jie
authors.initials: BJ
authors.lastname: Qin
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Shi-bo
authors.initials: SB
authors.lastname: Jiang
authors.forename: Lan
authors.initials: L
authors.lastname: Xie
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D015195:Drug Design; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D015394:Molecular Structure; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001562:Benzimidazoles; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase