Synthesis and antiviral evaluation of polyhalogenated imidazole nucleosides: Dimensional analogues of 2,5,6-trichloro-1-(β-D-ribofuranosyl) benzimidazole

Tun Cheng Chien, Sunita S. Saluja, John C. Drach, Leroy B. Townsend*

*此作品的通信作者

研究成果: 雜誌貢獻期刊論文同行評審

39 引文 斯高帕斯(Scopus)

摘要

A series of polyhalogenated imidazole nucleosides were designed and synthesized as ring-contracted analogues of 2,5,6-trichloro-1-(β-D- ribofuranosyl)benzimidazole (TCRB) and its 2-bromo analogue (BDCRB) in an effort to explore the spatial limitation of the active pocket(s) in the target protein(s). 2,4,5-Trichloro-, 2-bromo-4,5-dichloro-, and 2,4,5-tribromoimidazole nucleosides were prepared by a condensation of the preformed heterocycles with the appropriate sugar precursors. The ribofuranosyl and xylofuranosyl analogues were prepared by a direct glycosylation using the Vorbruggen's silylation method and provided exclusively the β-anomers. The arabinofuranosyl analogues were prepared by the sodium salt method to give both the α-and β-anomers. The absolute configurations were established by 1H NMR spectroscopy. Alkylation of the polyhalogenated imidazoles with the appropriate bromomethyl ethers gave the acyclic acyclovir and ganciclovir analogues. In general, the parent polyhalogenated imidazoles showed some activity against human cytomegalovirus (HCMV) (IC50 - 35 μM). However, with the exception of two tribromo analogues (7c, 13c-β), most of their nucleoside derivatives were inactive against both HCMV and herpes simplex virus type-1 (HSV-1) and were not cytotoxic. The results suggest that the ring-contracted nucleoside analogues of TCRB and BDCRB interacted weakly or not at all with viral and cellular targets.

原文英語
頁(從 - 到)5743-5752
頁數10
期刊Journal of Medicinal Chemistry
47
發行號23
DOIs
出版狀態已發佈 - 2004 11月 4
對外發佈

ASJC Scopus subject areas

  • 分子醫學
  • 藥物發現

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