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

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5743-5752
Number of pages10
JournalJournal of Medicinal Chemistry
Volume47
Issue number23
DOIs
Publication statusPublished - 2004 Nov 4

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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