title: The versatile nature of the 6-aminoquinolone scaffold: identification of submicromolar hepatitis C virus NS5B inhibitors.
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, 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 μM against NS5B polymerase and selective antiviral effect (EC50 = 3.03 μM) coupled with the absence of any cytostatic effect (CC50 > 163 μM; 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.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università degli Studi di Perugia , Via del Liceo 1, 06123 Perugia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Manfroni
authors.forename: Rolando
authors.initials: R
authors.lastname: Cannalire
authors.forename: Maria Letizia
authors.initials: ML
authors.lastname: Barreca
authors.forename: Neerja
authors.initials: N
authors.lastname: Kaushik-Basu
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Johan
authors.initials: J
authors.lastname: Winquist
authors.forename: Nunzio
authors.initials: N
authors.lastname: Iraci
authors.forename: Dinesh
authors.initials: D
authors.lastname: Manvar
authors.forename: Jan
authors.initials: J
authors.lastname: Paeshuyse
authors.forename: Rupa
authors.initials: R
authors.lastname: Guhamazumder
authors.forename: Amartya
authors.initials: A
authors.lastname: Basu
authors.forename: Stefano
authors.initials: S
authors.lastname: Sabatini
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.forename: U Helena
authors.initials: UH
authors.lastname: Danielson
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.forename: Violetta
authors.initials: V
authors.lastname: Cecchetti
mesh_terms: D000634:Aminoquinolines / Q000737:chemistry*; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D020349:Surface Plasmon Resonance; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000634:Aminoquinolines; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C025152:aminoquinolone; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase