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

2015; American Chemical Society; Volume: 58; Issue: 9 Linguagem: Inglês

10.1021/acs.jmedchem.5b00327

1520-4804

Sanjeev Kumar V. Vernekar, Li Qiu, Jing Zhang, Jayakanth Kankanala, Hongmin Li, Robert J. Geraghty, Zhengqiang Wang,

Click Chemistry and Applications

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).