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Structure-Based Discovery of Pyrazolobenzothiazine Derivatives As Inhibitors of Hepatitis C Virus Replication
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
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2013 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 56, no 6, 2270-2282 p.Article in journal (Refereed) Published
Abstract [en]

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 mu M, EC90 = 25.6 mu M, and CC50 > 180 mu M in the Huh 9-13 replicon system, thus providing a good starting point for further hit evolution.

Place, publisher, year, edition, pages
2013. Vol. 56, no 6, 2270-2282 p.
National Category
Natural Sciences
URN: urn:nbn:se:uu:diva-199464DOI: 10.1021/jm301643aISI: 000317032200009OAI: oai:DiVA.org:uu-199464DiVA: diva2:620307
Available from: 2013-05-08 Created: 2013-05-06 Last updated: 2013-05-08Bibliographically approved

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Danielson, U. Helena
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