Synthesis and biological activity of novel nonnucleoside inhibitors of HIV-1 reverse transcriptase. 2-Aryl-substituted benzimidazoles

Journal of Medicinal Chemistry
T RothChristopher J Michejda

Abstract

The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the act...Continue Reading

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