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Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication. 2013
Maria Letizia Barreca, and
Giuseppe Manfroni, and
Pieter Leyssen, and
Johan Winquist, and
Neerja Kaushik-Basu, and
Jan Paeshuyse, and
Ramalingam Krishnan, and
Nunzio Iraci, and
Stefano Sabatini, and
Oriana Tabarrini, and
Amartya Basu, and
U Helena Danielson, and
Johan Neyts, and
Violetta Cecchetti
Dipartimento di Chimica e Tecnologia del Farmaco, Sezione di Chimica Farmaceutica II, Università degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy. lbarreca@unipg.it
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.
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