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J Med Chem. 2015 May 14;58(9):4016-28. doi: 10.1021/acs.jmedchem.5b00327. Epub 2015 May 4.

5'-Silylated 3'-1,2,3-triazolyl Thymidine Analogues as Inhibitors of West Nile Virus and Dengue Virus.

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†Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
‡Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, New York 12208, United States.
§Department of Biomedical Sciences, School of Public Health, University at Albany, Albany, New York 12201, United States.


West Nile virus (WNV) and Dengue virus (DENV) are important human pathogens for which there are presently no vaccine or specific antivirals. We report herein a 5'-silylated nucleoside scaffold derived from 3'-azidothymidine (AZT) consistently and selectively inhibiting WNV and DENV at low micromolar concentrations. Further synthesis of various triazole bioisosteres demonstrated clear structure-activity relationships (SARs) in which the antiviral activity against WNV and DENV hinges largely on both the 5'-silyl group and the substituent of 3'-triazole or its bioisosteres. Particularly interesting is the 5' silyl group which turns on the antiviral activity against WNV and DENV while abrogating the previously reported antiviral potency against human immunodeficiency virus (HIV-1). The antiviral activity was confirmed through a plaque assay where viral titer reduction was observed in the presence of selected compounds. Molecular modeling and competitive S-adenosyl-l-methionine (SAM) binding assay suggest that these compounds likely confer antiviral activity via binding to methyltransferase (MTase).

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