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

摘要: The development of new nonnucleoside inhibitors 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 AIDS research. We used known inhibitor HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as lead structure for drug design with objective making more potent both wild-type (WT) and variant RTs. A series structurally related 1,2-substituted benzimidazoles was synthesized evaluated their ability inhibit vitro polymerization by WT RT. structure-activity study carried out compounds determine optimum groups substitution benzimidazole ring at N1 C2 positions. best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 440 nM) while retaining broad many clinically observed strains resistant inhibitors. Overall, amino acid is 4-fold or greater than TZB comparable other currently undergoing clinical trials, most which do not have capacity forms enzyme.