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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.
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