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-substituted 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 unsuitable as drug candidates. The primary source of instability is thought to be the anomeric bond. The synthesis of a series of chemically stable benzimidazole-2'-isonucleosides is presented. The synthetic schemes employed are based on nucleophilic displacements of a 2'-tosylate from carbohydrate intermediates with 2-bromo-5,6-dichlorobenzidazole. 2-Bromo and 2-isopropyl amino analogs with 3'- and 5'-oxo and deoxy substitutions were prepared. The benzimidazole-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.
Freeman
G A
GA
Division of Medicinal Chemistry, GlaxoWellcome Research, North Carolina 27709, USA.
Selleseth
D W
DW
Rideout
J L
JL
Harvey
R J
RJ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D003587:Cytomegalovirus / Q000187:drug effects*; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D006801:Humans; D066298:In Vitro Techniques; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D000998:Antiviral Agents; D001562:Benzimidazoles; D009705:Nucleosides