DESIGN, SYNTHESIS, AND ANTIVIRAL EVALUATION OF 2-SUBSTITUTED 4,5-DICHLORO-1-BETA-D-RIBOFURANOSYLBENZIMIDAZOLES AND 4,6-DICHLORO-1-BETA-D-RIBOFURANOSYLBENZIMIDAZOLES AS POTENTIAL AGENTS FOR HUMAN CYTOMEGALOVIRUS INFECTIONS

The syntheses of 2,4,6-trichlorobenzimidazole (4a) and 2-bromo-4,6-dic hlorobenzimidazole (4b) were accomplished via the 2-amino intermediate (3) using a mild diazotization procedure. Ribosylation of 4a and 4b a nd subsequent deprotection afforded the corresponding ,4,6-trichloro-1 -beta-D-ribofuranosylbenzimidazole (7a) and o-4,6-dichloro-1-beta-D-ri bofuranosylbenzimidazole (7b). The 2-azido (10), 2-amino (11), 2-thion e (13), 2-methylthio (14a), and 2-benzylthio (14b) derivatives were pr epared via displacement reactions at the 2-position of the 2,3,5-tri-O -acetyl derivative of 7a. 2,4,5-Trichlorobenzimidazole (17a) and 2-bro mo-4,5-dichlorobenzimidazole (17b) were synthesized from the correspon ding 1,2-phenylenediamines via successive cyclization with cyanogen br omide and diazotization in the presence of an appropriate cupric halid e. Ribosylation of compounds 17a and 17b was followed by deprotection to afford ,4,5-trichloro-1-beta-D-ribofuranosylbenzimidazole (20a), an d o-4,5-dichloro-1-beta-D-ribofuranosylbenzimidazole (20b). Heterocycl es (3, 4a, 17a) and nucleosides (7a,b, 8, 10, 11, 13, 14a,b, 20a,b) we re evaluated for activity against human cytomegalovirus (HCMV) and her pes simplex virus type 1 (HSV-1) and for cytotoxicity. The 2-chloro bu t not the 2-amino heterocycles were active against HCMV (IC50's = 5-8 mu M) but not HSV-1; both also were somewhat cytotoxic to uninfected c ells (IC50's = 32-100 mu M). Among the nucleosides, the 2-chloro and 2 -bromo analogs in both the 4,5- and 4,6-dichloro series (20a,b, 7a,b, respectively) were active against HCMV (IC50's = 1-10 mu M) and noncyt otoxic in their antiviral dose ranges. The 2-bromo compounds were more active than the 2-chloro analogs; the 2-azido and 2-thiobenzyl analog s (10, 14b) were weakly active against HCMV, but this activity was not well separated from cytotoxicity. None of the nucleosides were active against HSV-1. This pattern of activity and cytotoxicity is similar t o that of the 2-chloro- and 2-bromo-5,6-dichloro analogs (TCRB, BDCRB) which we reported previously. Although these new 4,5- and 4,6-dichlor o analogs are potent and selective inhibitors of HCMV, they are not as potent at TCRB and BDCRB.