DESIGN, SYNTHESIS, AND ANTIVIRAL EVALUATIONS OF 1-(SUBSTITUTED BENZYL)-2-SUBSTITUTED-5,6-DICHLOROBENZIMIDAZOLES AS NONNUCLEOSIDE ANALOGS OF,6-TRICHLORO-1-(BETA-D-RIBOFURANOSYL)BENZIMIDAZOLE

We have recently reported that certain ribosylated polyhalogenated ben zimidazoles are potent and selective inhibitors of HCMV replication at noncytotoxic concentrations. To extend the structure-activity relatio nship beyond these first-generation compounds, we alkylated 5,6-dichlo ro-2-substituted-benzimidazoles with either a series of substituted be nzyl halides or (2-bromoethyl)benzene to obtain five series of nonnucl eoside analogues. Evaluation of these compounds for activity against h erpes viruses revealed that the new compounds were less active than th e benzimidazole ribonucleosides against human cytomegalovirus (HCMV) a nd inactive against herpes simplex virus type 1 (HSV-1). However, as p art of our broader antiviral testing, we found that some of these comp ounds were active against HIV. Comparisons of the biological data reve aled that a chloro or bromo group was required at the 2-position for t he best separation of activity against HIV and cytotoxicity. Evaluatio n of the most active compounds against drug-resistant HIV suggested th at they act by a mechanism other than inhibition of reverse transcript ase.