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

Abstract

AbstractWe have recently found that 2,5,6‐trichloro‐1‐(β‐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[4,5‐b]quinoxaline nucleosides as linear dimensional analogs of the benzimidazole nucleosides 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]quinoxalines involving a reaction of 2,3,6,7‐tetrachloroquinoxaline with ammonia followed by a ring annulation as the key step. This furnished the versatile heterocycle 6,7‐dichloroimidazo[4,5‐b]quinoxalin‐2‐one. Ribosylation of 2‐substituted imidazo[4,5‐b]quinoxalines 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, that the binding pocket on the protein target of TCRB will tolerate some electronic and size changes.