Document Detail

Structure-based discovery of pyrazolobenzothiazine derivatives as inhibitors of hepatitis C virus replication.
MedLine Citation:
PMID:  23409936     Owner:  NLM     Status:  MEDLINE    
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.
Maria Letizia Barreca; Giuseppe Manfroni; 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
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-03-07
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  56     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-28     Completed Date:  2013-05-23     Revised Date:  2014-03-31    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2270-82     Citation Subset:  IM    
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MeSH Terms
Antiviral Agents / chemical synthesis,  chemistry,  pharmacology
Drug Design*
Hepacivirus / drug effects*,  enzymology,  physiology*
Models, Molecular
Protein Conformation
Pyrazoles / chemical synthesis,  chemistry*,  pharmacology*
Viral Nonstructural Proteins / antagonists & inhibitors,  chemistry,  metabolism
Virus Replication / drug effects*
Grant Support
Reg. No./Substance:
0/Antiviral Agents; 0/NS-5 protein, hepatitis C virus; 0/Pyrazoles; 0/Viral Nonstructural Proteins; 3QD5KJZ7ZJ/pyrazole

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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