SYNTHESIS AND BIOLOGICAL-ACTIVITY OF NOVEL NONNUCLEOSIDE INHIBITORS OF HIV-1 REVERSE-TRANSCRIPTASE - 2-ARYL-SUBSTITUTED BENZIMIDAZOLES

The development of new nonnucleoside inhibitors of human immunodeficie ncy 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, difluorophenyl) -1H,3H-thiazolo[3,4-a]benzimidazole (TZB), as the lead structure for d rug 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 thei r ability to inhibit in vitro polymerization by HIV-1 WT RT. A structu re- activity study was carried out for the series of compounds to dete rmine the optimum groups; for substitution of the benzimidazole ring a t the N1 and C2 positions. The best inhibitor, nzyl)-2-(2,6-difluoroph enyl)-4-methylbenzimidazole (35), has an IC50 = 200 nM against HIV-1 W T RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV- infected MT-4 cells revealed that 35 had strong antiviral activity (EC 50 = 440 nM) against wild-type virus while retaining broad activity;ag ainst many clinically observed HIV-1 strains resistant to nonnucleosid e inhibitors. Overall, the activity of 35 against wild-type and resist ant strains with amino acid substitution in RT is 4-fold or greater th an that of TZB and is comparable to that of other nonnucleoside inhibi tors currently undergoing clinical trials, most of which do not have t he capacity to inhibit the variant forms of the enzyme.