Design, synthesis, and biological evaluation of tricyclic nucleosides (dimensional probes) as analogues of certain antiviral polyhalogenated benzimidazole ribonucleosides

The polyhalogenated benzimidazole nucleosides 2,5,6-trichloro-1-(beta-D-rib ofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synth esized in our laboratory and established as potent and selective inhibitors of human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure in a dimensionally extended m anner and probe the spatial limitation of the target enzyme(s), a series of 2-substituted 6,7-dichloro-1-(beta-D-ribofuranosyl)naphtho[2,3-d]imidazole s and the N1- and N3-ribonucleosides of 2-substituted 6,7-dichloroimidazo[4 ,5-b]quinolines were prepared. The nucleosides 6,7-dichloro-1-(beta-D-ribof uranosyl)imidazo[4,5-b]quinolin-2-one and 6,7-dichloro-3-(beta-D-ribofurano syl)imidazo[4,5-b]quinolin-2-one were selected and used as the key syntheti c intermediates in the imidazo[4,5-b]quinoline series. Evaluation of the co mpounds for activity against HCMV and herpes simplex virus type 1 revealed that the trichloro analogues of TCRB (2a, 3a) were nearly as active against HCMV as TCRB but were more cytotoxic. The results suggest that extending t he heterocycle of TCRB affected the affinity for the HCMV target only sligh tly but increased the affinity for cellular enzymes.