Design, Synthesis, and Antiviral Activity of Certain 2,5,6-Trihalo-1-(.beta.-D-ribofuranosyl)benzimidazoles

Abstract

A new series of 2-substituted 5,6-dichlorobenzimidazole ribonucleosides has been synthesized and tested for activity against two human herpes viruses and for cytotoxicity. 2,5,6-Trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) was prepared by ribosylation of the heterocycle 2,5,6-trichlorobenzimidazole followed by a removal of the protecting groups. 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 followed by nonaqueous diazotization and removal of the blocking groups. Biological evaluation revealed marked differences in the activities of these compounds and the closely related known compound 5,6-dichloro-1-(beta-D-ribofuranosyl)benzimidazole (DRB). DRB was weakly active against both human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), (IC50's = 42 and 30 microM, respectively) but was cytotoxic to uninfected human foreskin fibroblasts and KB cells in the same dose range. Similar results were obtained with the heterocycle 2,5,6-trichlorobenzimidazole. In marked contrast, the ribonucleoside of 2,5,6-trichlorobenzimidazole (TCRB) was active against HCMV (IC50 = 2.9 microM, plaque assay; IC90 = 1.4 microM, yield assay) but only weakly active against HSV-1 (IC50 = 102 microM, plaque assay). Little to no cytotoxicity was observed in HFF and KB cells at concentrations up to 100 microM. By changing the substituent at the 2-position from chlorine to bromine (BDCRB), a 4-fold increase in activity against HCMV was observed without any significant increase in cytotoxicity. In contrast, the 2-I and 2-NH2 derivatives were only weakly active against HCMV and HSV-1 with activity not well-separated from cytotoxicity. These data establish that for maximum activity against HCMV with separation from cytotoxicity, ribose is preferred at the 1-position and that Cl or Br is apparently preferred at the 2-position. The activity and selectivity of both TCRB and BDCRB were better than that observed with either ganciclovir or foscarnet.

Resistance of Human Cytomegalovirus to the Benzimidazole l -Ribonucleoside Maribavir Maps to UL27

“…BDCRB was synthesized in the laboratory of L. B. Townsend as previously described (34). Maribavir was synthesized at GlaxoSmithKline (22) and was provided through the courtesy of K. K. Biron.…”

“…In 1995, we reported the synthesis and antiviral activity of TCRB and its 2-bromo analog, BDCRB (34) (Fig. 1).…”

Differences in DNA Packaging Genes and Sensitivity to Benzimidazole Ribonucleosides between Human Cytomegalovirus Strains AD169 and Towne

“…Thus, mapping of benzimidazole ribonucleoside resistance to packaging genes is consistent with the observed inhibition An evaluation of data from a number of antiviral susceptibility assays in our laboratory suggested HCMV strain AD169 was more sensitive to the benzimidazole ribonucleosides than HCMV strain Towne. The assays were performed as previously described (Townsend et al, 1995). Briefly, HFF cells in 24-well cluster dishes were infected with approximately 100 p.f.u.…”

Novel synthetic bisbenzimidazole that targets angiogenesis in Ehrlich ascites carcinoma bearing mice

“…[5][6][7] Multiple previous reports have suggested that benzimidazoles to be very good cytotoxic agents against different types of cancer cell lines. 8 Recently bisbenzimidazole conjugates have been reported to target mitochondria in cancer cells and induce their antiproliferative activity by caspase dependent apoptosis.…”