The syntheses of 2,4,6-trichlorobenzimidazole (4a) and 2-bromo-4,6-dichlorobenzimidazole (4b) were accomplished via the 2-amino intermediate (3) using a mild diazotization procedure. Ribosylation of 4a and 4b and subsequent deprotection afforded the corresponding 2,4,6-trichloro-1-beta-D-ribofuranosylbenzimidazole (7a) and 2-bromo-4,6-dichloro-1-beta-D-ribofuranosylbenzimidazole (7b). The 2-azido (10), 2-amino (11), 2-thione (13), 2-methylthio (14a), and 2-benzylthio (14b) derivatives were prepared 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-bromo-4,5-dichlorobenzimidazole (17b) were synthesized from the corresponding 1,2-phenylenediamines via successive cyclization with cyanogen bromide and diazotization in the presence of an appropriate cupric halide. Ribosylation of compounds 17a and 17b was followed by deprotection to afford 2,4,5-trichloro-1-beta-D-ribofuranosylbenzimidazole (20a), and 2-bromo-4,5-dichloro-1-beta-D-ribofuranosylbenzimidazole (20b). Heterocycles (3, 4a, 17a) and nucleosides (7a, b, 8, 10, 11, 13, 14a,b, 20a,b) were evaluated for activity against human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1) and for cytotoxicity. The 2-chloro but not the 2-amino heterocycles were active against HCMV (IC50's = 5-8 microM) but not HSV-1; both also were somewhat cytotoxic to uninfected cells (IC50's = 32-100 microM). 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 microM) and noncytotoxic in their antiviral dose ranges. The 2-bromo compounds were more active than the 2-chloro analogs; the 2-azido and 2-thiobenzyl analogs (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 to 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-dichloro analogs are potent and selective inhibitors of HCMV, they are not as potent at TCRB and BDCRB.