| Abstract
| - The syntheses of 2,4,6-trichlorobenzimidazole (4a) and2-bromo-4,6-dichlorobenzimidazole (4b)were accomplished via the 2-amino intermediate (3) using amild diazotization procedure.Ribosylation of 4a and 4b and subsequentdeprotection afforded the corresponding 2,4,6-trichloro-1-β-d-ribofuranosylbenzimidazole (7a)and 2-bromo-4,6-dichloro-1-β-d-ribofuranosylbenzimidazole (7b). The 2-azido (10), 2-amino(11), 2-thione (13), 2-methylthio(14a), and2-benzylthio (14b) derivatives were prepared viadisplacement reactions at the 2-position ofthe 2,3,5-tri-O-acetyl derivative of 7a.2,4,5-Trichlorobenzimidazole (17a) and2-bromo-4,5-dichlorobenzimidazole (17b) were synthesized from thecorresponding 1,2-phenylenediaminesvia successive cyclization with cyanogen bromide and diazotization inthe presence of anappropriate cupric halide. Ribosylation of compounds17a and 17b was followed bydeprotectionto afford2,4,5-trichloro-1-β-d-ribofuranosylbenzimidazole(20a), and 2-bromo-4,5-dichloro-1-β-d-ribofuranosylbenzimidazole (20b).Heterocycles (3, 4a, 17a) and nucleosides(7a,b, 8, 10,11, 13, 14a,b, 20a,b) wereevaluated for activity against human cytomegalovirus (HCMV)andherpes simplex virus type 1 (HSV-1) and for cytotoxicity. The2-chloro but not the 2-aminoheterocycles were active against HCMV (IC50's = 5−8μM) but not HSV-1; both also weresomewhat cytotoxic to uninfected cells (IC50's =32−100 μM). Among the nucleosides, the2-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 μM) andnoncytotoxic in their antiviral dose ranges.The 2-bromo compounds were more active than the 2-chloro analogs;the 2-azido and2-thiobenzyl analogs (10, 14b) were weakly activeagainst HCMV, but this activity was notwell separated from cytotoxicity. None of the nucleosides wereactive against HSV-1. Thispattern of activity and cytotoxicity is similar to that of the2-chloro- and 2-bromo-5,6-dichloroanalogs (TCRB, BDCRB) which we reported previously. Although thesenew 4,5- and 4,6-dichloro analogs are potent and selective inhibitors of HCMV, they arenot as potent at TCRBand BDCRB.
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