New Pyrazolobenzothiazine Derivatives as Hepatitis C Virus NS5B Polymerase Palm Site I Inhibitors

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• 作者：Giuseppe Manfroni ; Dinesh Manvar ; Maria Letizia Barreca ; Neerja Kaushik-Basu ; Pieter Leyssen ; Jan Paeshuyse ; Rolando Cannalire ; Nunzio Iraci ; Amartya Basu ; Maxim Chudaev ; Claudio Zamperini ; Elena Dreassi ; Stefano Sabatini ; Oriana Tabarrini ; Johan Neyts ; Violetta Cecchetti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 24, 2014
• 年：2014
• 卷：57
• 期：8
• 页码：3247-3262
• 全文大小：522K
• 年卷期：v.57,no.8(April 24, 2014)
• ISSN：1520-4804

文摘

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 渭M against NS5B polymerase and antiviral effect (EC₅₀ = 8.1 渭M; EC₉₀ = 23.3 渭M) coupled with the absence of any antimetabolic effect (CC₅₀ > 224 渭M; 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.