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.
The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors / Manfroni, Giuseppe; Cannalire, Rolando; Barreca Maria, Letizia; Kaushik-Basu, Neerja; Leyssen, Pieter; Winquist, Johan; Iraci, Nunzio; Manvar, Dinesh; Paeshuyse, Jan; Guhamazumder, Rupa; Basu, Amartya; Sabatini, Stefano; Tabarrini, Oriana; Danielson U., Helena; Neyts, Johan; Cecchetti, Violetta. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 57:5(2014), pp. 1952-1963. [10.1021/jm401362f]
The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors
Cannalire Rolando;Cecchetti Violetta
2014
Abstract
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.