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, 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 IC50 value of 0.069 μM against NS5B polymerase and selective antiviral effect (EC50 = 3.03 µM, EC90 =13.5 μM) coupled with the absence of any cytostatic effect (CC50 >163 µM, SI >54) in a HCV subgenomic replicon system. These results clearly indicate that the 6-aminoquinolone scaffold is worthy of further investigation in the context of NS5B-targeted HCV drug discovery programs.