Design, synthesis and biologic evaluation of diarylbenzimidazole derivatives as novel HIV-1 non-nucleoside reverse transcriptase inhibitors / 药学学报
Acta Pharmaceutica Sinica
; (12): 1233-1243, 2009.
Article
in Zh
| WPRIM
| ID: wpr-344088
Responsible library:
WPRO
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.
Full text:
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Index:
WPRIM
Main subject:
Pharmacology
/
Physiology
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Structure-Activity Relationship
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Virus Replication
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Benzimidazoles
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Drug Design
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Molecular Structure
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Cell Line
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Chemistry
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HIV-1
Limits:
Humans
Language:
Zh
Journal:
Acta Pharmaceutica Sinica
Year:
2009
Type:
Article