title: C-6 aryl substituted 4-quinolone-3-carboxylic acids as inhibitors of hepatitis C virus.
abstract: Quinolone-3-carboxylic acid represents a highly privileged chemotype in medicinal chemistry and has been extensively explored as antibiotics and antivirals targeting human immunodeficiency virus (HIV) integrase (IN). Herein we describe the synthesis and anti-hepatitis C virus (HCV) profile of a series of C-6 aryl substituted 4-quinlone-3-carboxylic acid analogues. Significant inhibition was observed with a few analogues at low micromolar range against HCV replicon in cell culture and a reduction in replicon RNA was confirmed through an RT-qPCR assay. Interestingly, evaluation of analogues as inhibitors of NS5B in a biochemical assay yielded only modest inhibitory activities, suggesting that a different mechanism of action could operate in cell culture.
authors: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors: Yue-Lei
authors: YL
authors: Chen
authors: Jeana
authors: J
authors: Zacharias
authors: Robert
authors: R
authors: Vince
authors: Robert J
authors: RJ
authors: Geraghty
authors: Zhengqiang
authors: Z
authors: Wang
mesh_terms: D042462:4-Quinolones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D060888:Real-Time Polymerase Chain Reaction; D012093:Replicon / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D042462:4-Quinolones; D000998:Antiviral Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D017361:Viral Nonstructural Proteins; C576632:4-quinolone-3-carboxylic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase