Benzimidazole 2 '-isonucleosides: Design, synthesis, and antiviral activity of 2-substituted-5,6-dichlorobenzimidazole 2 '-isonucleosides

2,5,6-Trihalogenated benzimidazole-beta-D-ribofuranosyl nucleosides and 2-s ubstituted amino-5,6-dichlorobenzimidazole-beta-L-ribofuranosyl nucleosides are potent and selective inhibitors of human cytomegalovirus (HCMV). The D -ribofuranosyl analogs are metabolized rapidly in vivo rendering them unsui table as drug candidates. The primary source of instability is thought to b e the anomeric bond. The synthesis of a series of chemically stable benzimi dazole-2'-isonucleosides is presented. The synthetic schemes employed are b ased on nucleophilic displacements bf a 2'-tosylate from carbohydrate inter mediates with 2-bromo-5,6-dichlorobenzidazole. 2-Bromo and 2-isopropyl amin o analogs with 3'- and 5'-oxo and deoxy substitutions were prepared. The be nzimidazole-2'-isonucleosides presented here demonstrated reduced activity against HCMV when compared to other D-ribofuranosyl benzimidazole analogs. In addition, they were not found to be inhibitors of HIV.