Synthesis of Imidazo[4,5-b]quinoxaline Ribonucleosides as Linear Dimensional Analogs of Antiviral Polyhalogenated Benzimidazole Ribonucleosides

Wehave recently found that 2,5,6-trichloroH~-D-ribofuranosyl)benzimidazole(TCRB) and the corresponding 2-bromo analog have better in vitro activities against HCMV than the clinically used agents ganciclovir and foscarnet, These benzimidazole nucleosides act by a unique mechanism, however, their biological target has not been completely identified. As an approach to probing the target, we have designed imidazo[4,S-b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole uucleosides to study the spatial limitation of the binding site in the target enzyme. A convenient route was developed for the synthesis of 2-substituted 6,7-dichloroimidazo[4,5-b]quinoxaiines involving a reaction of 2,3,6,7tetrachloroquinoxaliue with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7-dichloroimidazo[4,5-b]quinoxatin-2-one. Ribosylation of 2-substituted imidazo[4,5b]quinoxaiines was influenced by the functional group at the 2-position and the 2-one compound was found to smoothly undergo ribosylation. The 2-one group of the nucleoside was converted into specifically selected 2-substituted compounds. Evaluation of the compounds for activity against two herpesviruses and for cytotoxicity showed they were less active and/or more cytotoxic than TCRB. We conclude therefore, thai the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.