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

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

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 mu M against NS5B polymerase and selective antiviral effect (EC50 = 3.03 mu M) coupled with the absence of any cytostatic effect (CC50 > 163 mu M; SI > 54) in Huh 9-13 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.

Ingår i:Journal of Medicinal Chemistry: American Chemical Society (ACS)57:5, s. 1952-19630022-26231520-4804

Av författaren/redakt...: Manfroni, Giusep ...; Cannalire, Rolan ...; Barreca, Maria L ...; Kaushik-Basu, Ne ...; Leyssen, Pieter; Winquist, Johan; visa fler...; Iraci, Nunzio; Manvar, Dinesh; Paeshuyse, Jan; Guhamazumder, Ru ...; Basu, Amartya; Sabatini, Stefan ...; Tabarrini, Orian ...; Danielson, U. He ...; Neyts, Johan; Cecchetti, Viole ...; visa färre...

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