Design, synthesis and biologic evaluation of diarylbenzimidazole derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors.
- Author:
Bing-jie QIN
1
;
Ting ZHOU
;
Hong LU
;
Shi-bo JIANG
;
Lan XIE
Author Information
1. Institute ofPharmacology and Toxicology, Academy of Military Medical Sciences, Beijing 100850, China.
- Publication Type:Journal Article
- MeSH:
Anti-HIV Agents;
chemical synthesis;
chemistry;
pharmacology;
Benzimidazoles;
chemical synthesis;
chemistry;
pharmacology;
Cell Line;
Drug Design;
HIV Reverse Transcriptase;
antagonists & inhibitors;
HIV-1;
physiology;
Humans;
Molecular Structure;
Reverse Transcriptase Inhibitors;
chemical synthesis;
chemistry;
pharmacology;
Structure-Activity Relationship;
Virus Replication;
drug effects
- From:
Acta Pharmaceutica Sinica
2009;44(11):1233-1243
- CountryChina
- Language:Chinese
-
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.
