Synthesis and antiviral activity of certain 5'-modified analogs of 2,5,6-trichloro-1-(β-D-ribofuranosyl)benzimidazole

A series of 5‘-modified 2,5,6-trichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpesviruses and for cytotoxicity. The 5‘-methoxy, 5‘-ethoxy, and 5‘-butoxy analogs of 2,5,6-trichloro-1-(β-d-ribofuranosyl)benzimidazole (TCRB) were prepared by coupling the appropriate 5-O-alkyl-1,2,3-tri-O-acetyl-β-d-ribose derivatives with 2,5,6-trichlorobenzimidazole followed by removal of the protecting groups. The 5‘-deoxy-5‘-fluoro, -5‘-chloro, -5‘-bromo, -5‘-iodo, -5‘-azido, and -5‘-thiomethyl derivatives were synthesized in a similar fashion. All of these 5‘-modified derivatives had significant activity against HCMV in plaque and yield reduction assays (IC50's = 0.5−14.2 μM) but had little activity (IC50's > 100 μM) against HSV-1. This pattern is similar to the antiviral activity profile observed for TCRB. The 5‘-halogenated derivatives were more active than the other 5‘-modified derivatives with antiviral activity well separated from cytotoxicity. In general, cyto...