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Title: New Pyrazolobenzothiazine Derivatives as Hepatitis C Virus NS5B Polymerase Palm Site I Inhibitors
Authors: Giuseppe, Manfroni
Dinesh, Manvar
Maria, Letizia Barreca
Neerja, Kaushik Basu
Pieter, Leyssen
Jan, Paeshuyse
Rolando, Cannalire
Nunzio, Iraci
Amartya, Basu
Maxim, Chudaev
Zamperini, Claudio
Dreassi, Elena 
Stefano, Sabatini
Oriana, Tabarrini
Johan, Neyts
Violetta, Cecchetti
Issue Date: 2014
Project: None 
We have previously identified the pyrazolobenzothiazine scaffold as a promising chemotype against hepatitis C virus (HCV) NS5B polymerase, a validated and promising anti-HCV target. Herein we describe the design, synthesis, enzymatic, and cellular characterization of new pyrazolobenzothiazines as anti-HCV inhibitors. The binding site for a representative derivative was mapped to NS5B palm site I employing a mutant counterscreen assay, thus validating our previous in silico predictions. Derivative 2b proved to be the best selective anti-HCV derivative within the new series, exhibiting a IC50 of 7.9 μM against NS5B polymerase and antiviral effect (EC50 = 8.1 μM; EC90 = 23.3 μM) coupled with the absence of any antimetabolic effect (CC50 > 224 μM; SI > 28) in a cell based HCV replicon system assay. Significantly, microscopic analysis showed that, unlike the parent compounds, derivative 2b did not show any significant cell morphological alterations. Furthermore, since most of the pyrazolobenzothiazines tested altered cell morphology, this undesired aspect was further investigated by exploring possible perturbation of lipid metabolism during compound treatment.
ISSN: 0022-2623
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