DESIGN, SYNTHESIS, AND ANTIVIRAL ACTIVITY OF CERTAIN 5,6-TRIHALO-1-(BETA-D-RIBOFURANOSYL)BENZIMIDAZOLES

A new series of 2-substituted 5,6-dichlorobenzimidazole ribonucleoside s has been synthesized and tested for activity against two human herpe s viruses and for cytotoxicity. ,6-Trichloro-1-(beta-D-ribofuranosyl)b enzimidazole (TCRB) was prepared by ribosylation of the heterocycle 2, 5,6-trichlorobenzimidazole followed by a removal of the protecting gro ups. The 2-bromo derivative (BDCRB) was made in a similar fashion from 2-bromo-5,6-dichlorobenzimidazole. In contrast, the 2-iodo derivative presented a more difficult problem since the appropriate heterocycle was unavailable. This prompted us to prepare the 2-amino derivative fo llowed by nonaqueous diazotization and removal of the blocking groups. Biological evaluation revealed marked differences in the activities o f these compounds and the closely related known compound 5,6-dichloro- 1-(beta-D-ribofuranosyl)benzimidazole (DRB). DRB was weakly active aga inst both human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), (IC50's = 42 and 30 mu M, respectively) but-was cytotoxic to uninfected human foreskin fibroblasts and KB cells in the same dose r ange. Similar results were obtained with the heterocycle 2,5,6-trichlo robenzimidazole. In marked contrast, the ribonucleoside of 2,5,6-trich lorobenzimidazole (TCRB) was active against HCMV (IC50 = 2.9 mu M, pla que assay; IC50 = 1.4 mu M, yield assay) but only weakly active agains t HSV-1 (IC50 = 102 mu M, plaque assay). Little to no cytotoxicity was observed in HFF and KB cells at concentrations up to 100 mu M. By cha nging the substituent at the 2-position from chlorine to bromine (BDCR B), a 4-fold increase in activity against HCMV was observed without an y significant increase in cytotoxicity. In contrast, the 2-I and 2-NH2 derivatives were only weakly active against HCMV and HSV-1 with activ ity not well-separated from cytotoxicity. These data establish that fo r maximum activity against HCMV with separation from cytotoxicity, rib ose is preferred at the 1-position and that Cl or Br is apparently pre ferred at the 2-position. The activity and selectivity of both TCRB an d BDCRB were better than that observed with either ganciclovir or fosc arnet.