The Versatile Nature of the 6-Aminoquinolone Scaffold: Identification of Submicromolar Hepatitis C Virus NS5B Inhibitors

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• 作者：Giuseppe Manfroni ; Rolando Cannalire ; Maria Letizia Barreca ; Neerja Kaushik-Basu ; Pieter Leyssen ; Johan Winquist ; Nunzio Iraci ; Dinesh Manvar ; Jan Paeshuyse ; Rupa Guhamazumder ; Amartya Basu ; Stefano Sabatini ; Oriana Tabarrini ; U. Helena Danielson ; Johan Neyts ; Violetta Cecchetti
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1952-1963
• 全文大小：444K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

We have previously reported that the 6-aminoquinolone chemotype is a privileged scaffold to obtain antibacterial and antiviral agents. Herein we describe the design, synthesis, and enzymatic and cellular characterization of new 6-aminoquinolone derivatives as potent inhibitors of NS5B polymerase, an attractive and viable therapeutic target to develop safe anti-HCV agents. The 6-amino-7-[4-(2-pyridinyl)-1-piperazinyl]quinolone derivative 8 proved to be the best compound of this series, exhibiting an IC₅₀ value of 0.069 渭M against NS5B polymerase and selective antiviral effect (EC₅₀ = 3.03 渭M) coupled with the absence of any cytostatic effect (CC₅₀ > 163 渭M; SI > 54) in Huh聽9鈥?3 cells carrying a HCV genotype 1b, as measured by MTS assay. These results indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs.