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American Chemical Society, Journal of Medicinal Chemistry, 6(56), p. 2270-2282, 2013

DOI: 10.1021/jm301643a

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Structure-Based Discovery of Pyrazolobenzothiazine Derivatives As Inhibitors of Hepatitis C Virus Replication

Journal article published in 2013 by Maria Letizia Barreca ORCID, Giuseppe Manfroni ORCID, Pieter Leyssen, Johan Winquist, Neerja Kaushik-Basu, Jan Paeshuyse, Ramalingam Krishnan, Nunzio Iraci, Stefano Sabatini, Oriana Tabarrini, Amartya Basu, U. Helena Danielson, Johan Neyts, Violetta Cecchetti ORCID, Others
This paper is available in a repository.
This paper is available in a repository.

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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.