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Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base

McGuigan, Christopher, Yarnold, Christopher J., Jones, Garry, Velázquez, Sonsoles, Barucki, Hubert, Brancale, Andrea, Andrei, Graciela, Snoeck, Robert, De Clercq, Erik and Balzarini, Jan 1999. Potent and selective inhibition of varicella-zoster virus (VZV) by nucleoside analogues with an unusual bicyclic base. Journal of Medicinal Chemistry 42 (22) , pp. 4479-4484. 10.1021/jm990346o

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Abstract

We herein report the discovery of an entirely new category of potent antiviral agents based on novel deoxynucleoside analogues with unusual bicyclic base moieties. Target structures, previously known as byproducts in Pd-catalyzed coupling of terminal alkynes with 5-iodonucleosides, are recognized herein for the first time to be potent and selective inhibitors of varicella-zoster virus (VZV) in vitro. As an unusual structure-activity relationship we noted the absolute requirement of a long alkyl side chain, with an optimum length of C8-C10, for antiviral activity. We thus report the synthesis and characterization of a series of chain-modified analogues and their extensive in vitro evaluation. The lead compounds have a ca. 300-fold enhancement in anti-VZV activity over the reference compound acyclovir, with no detectable in vitro cytotoxicity. The novel structure of these compounds, coupled with their ease of synthesis, excellent antiviral profile, and promising physical properties, makes them of great interest for possible antiviral drug development.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RS Pharmacy and materia medica
ISSN: 0022-2623
Last Modified: 18 Oct 2017 13:44
URI: http://orca-mwe.cf.ac.uk/id/eprint/7480

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