Title: Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication
Authors: Barreca, Maria Letizia ×
Manfroni, Giuseppe
Leyssen, Pieter
Winquist, Johan
Kaushik-Basu, Neerja
Paeshuyse, Jan
Krishnan, Ramalingam
Iraci, Nunzio
Sabatini, Stefano
Tabarrini, Oriana
Basu, Amartya
Danielson, U Helena
Neyts, Johan
Cecchetti, Violetta #
Issue Date: Mar-2013
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:56 issue:6 pages:2270-82
Article number: 10.1021/jm301643a
Abstract: The NS5B RNA-dependent RNA polymerase is an attractive target for the development of novel and selective inhibitors of hepatitis C virus replication. To identify novel structural hits as anti-HCV agents, we performed structure-based virtual screening of our in-house library followed by rational drug design, organic synthesis, and biological testing. These studies led to the identification of pyrazolobenzothiazine scaffold as a suitable template for obtaining novel anti-HCV agents targeting the NS5B polymerase. The best compound of this series was the meta-fluoro-N-1-phenyl pyrazolobenzothiazine derivative 4a, which exhibited an EC50 = 3.6 μM, EC90 = 25.6 μM, and CC50 > 180 μM in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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