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

J Med Chem. 2014 Mar 13;57(5):1952-63. doi: 10.1021/jm401362f. Epub 2013 Nov 6.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoquinolines / chemistry*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Cell Line
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology
  • Hepacivirus / genetics
  • Humans
  • Magnetic Resonance Spectroscopy
  • Molecular Docking Simulation
  • Surface Plasmon Resonance
  • Viral Nonstructural Proteins / antagonists & inhibitors*


  • Aminoquinolines
  • Antiviral Agents
  • Enzyme Inhibitors
  • NS-5 protein, hepatitis C virus
  • Viral Nonstructural Proteins
  • aminoquinolone