The mosquito borne West Nile Virus (WNV), a member of Flaviviridae family, is one of the major emerging pathogen to humans and animals. This mosquito borne pathogen has spread rapidly across multiple continents during the last decade resulting in significant disease threat to humans and animals including fatalities and severe illness such as encephalitis and meningitis. Despite the growing public health concern associated with WNV infection, till date there have been no successful antiviral therapies and vaccines for human use against WNV. To discover potent inhibitors of WNV NS2B-NS3 serine protease, a library of 110 commercially available compounds with scaffolds that have a history of antimicrobial and antiviral activities were screened using the high-throughput screening (HTS) WNV assay. The most promising 'hit' compound 2-(5-(4-aminophenyl)-4-methyl-4H-1,2,4-triazol-3-ylthio)-N-(2-(2-(benzylamino)-2-oxoethylthio)benzo[d]thiazol-6-yl)acetamide found and its derivatives were subsequently synthesized and evaluated for their inhibitory activities against the WNV NS2B/NS3 protease. The most potent novel inhibitor from this class of compounds showed uncompetitive inhibition against WNV NS2B-NS3 protease with Ki of 2.77 � 0.13 �M.

Synthesis and biological evaluation of West Nile Virus NS2B-NS3 protease inhibitors

243rd National Meeting (2012)

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