Synthesis and Biological Activity of Novel Nonnucleoside Inhibitors of HIV-1 Reverse Transcriptase. 2-Aryl-Substituted Benzimidazoles

TLDR

Developing new nonnucleoside inhibitors of HIV‑1 reverse transcriptase that remain active against drug‑induced mutations is a critical goal in AIDS research. The authors aimed to create more potent inhibitors for both wild‑type and variant RTs by using the known inhibitor TZB as a lead structure. They synthesized a series of 1,2‑substituted benzimidazoles derived from TZB, evaluated their ability to inhibit HIV‑1 WT RT polymerization in vitro, and performed structure‑activity studies to optimize substitutions at the N1 and C2 positions. The optimized compound 35 exhibited an IC50 of 200 nM against WT RT, an EC50 of 440 nM in MT‑4 cell assays, and 4‑fold or greater activity than TZB against resistant strains, matching the potency of other clinical‑trial nonnucleoside inhibitors.

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 activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.