- 作者: Zhijian Zhu ; Sunita Saluja ; John C. Drach ; Leroy B. Townsend
- 作者服務機構: Department of Chemistry, College of Literature, Sciences, and Arts, University of Michigan, U.S.A.
- 中文摘要: We 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-dubdtituted 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 of TCRB will tolerate some electronic and size changes.
- 英文摘要: --
- 中文關鍵字: Herpes Virus; Antiviral; Nucleoside; Benzimidazole; Imidazo Quinoxaline; Polyhalogenation
- 英文關鍵字: 疹病毒;抗病毒;核;苯并咪唑;咪唑喏;聚鹵化