Design, synthesis, and antiviral evaluation of 2-deoxy-D-ribosides of substituted benzimidazoles as potential agents for human cytomegalovirus infections

Stereoselective glycosylation of 2,5,6-trichlorobenzimidazole (1b), 2-bromo -5,6-dichlorobenzimidazole (Ic), 5,6-dichlorobenzimidazole (Id), 5,6-dichlo robenzimidazole-2-thione (1e), 5,6-dichloro-2-(methylthio)benzimidazole (1f ), 2-(benzylthio)-5,6-dichlorobenzimidazole (1g), and 2-chloro-5,6-dimethyl benzimidazole (Ih) with 2-deoxy-3,5-di-O-p-toluoyl-alpha-D-erythro-pentofur anosyl chloride was achieved to give the desired beta nucleosides 2b-h. Sub sequent deprotection afforded the corresponding free beta-D-2-deoxyriboside s 3b-h. The 2-methoxy derivative 3i was synthesized by the treatment of 2b with methanolic sodium methoxide. Displacement of the 2-chloro group of 2b with lithium azide followed by a removal of the protective groups gave the 2-azido-5,6-dichlorobenzimidazole derivative (5). The 2-amino derivative (6 ) was obtained by hydrogenolysis of 5 over Raney nickel. 5,6-Dichloro-2-iso propylamino-1- (2-deoxy-beta-D-erythro-pentofuranosyl)benzimidazole (10) wa s prepared using 2'-deoxyuridine (7), N-deoxyribofuranosyl transferase and Id followed by functionalization of the C2 position. Antiviral evaluation o f target compounds established that compounds 3b and 3c were active against human cytomegalovirus (HCMV) at non-cytotoxic concentrations. The activity of these 2-deoxy ribosides, however, was less than the activity of the par ent riboside, 2,5,6-trichloro-1-beta-D-ribofuranosylbenzimidazole (TCRB). C ompared to TCRB, 3b and 3c were somewhat more cytotoxic and active against herpes simplex virus type 1. Compounds 3d-i with other substituents in the 2-position were inactive against both viruses and non-cytotoxic. In contras t, compounds with amine substituents in the 2-position (5, 6, 10) were acti ve against HCMV albeit less so than TCRB. These results establish that 2-de oxy-D-ribosyl benzimidazoles are less active against the DNA virus HCMV tha n are the corresponding D-ribosides.