The design, synthesis and biological evaluations of C-6 or C-7 substituted 2-hydroxyisoquinoline-1,3-diones as inhibitors of hepatitis C virus

• Published in: Bioorganic & medicinal chemistry 2012-01, Vol.20 (1), p.467-479
• Main Authors: Chen, Yue-Lei, Tang, Jing, Kesler, Matthew J., Sham, Yuk Y., Vince, Robert, Geraghty, Robert J., Wang, Zhengqiang
• Format: Article
• Language: English
• Subjects: 2-Hydroxyisoquinoline-1,3-dione; active sites; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Binding Sites; Biological and medical sciences; Catalytic Domain; chemotypes; Computer Simulation; Cyclization; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepatitis C virus; Hepatitis C virus (HCV); Human immunodeficiency virus; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Medical sciences; NS5B polymerase; Pharmacology. Drug treatments; replicon; ribonucleases; Structure-Activity Relationship; synthesis; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.10.058

C7-Substituted 2-hydroxyisoquinoline-1,3-diones inhibit the strand transfer of HIV integrase (IN) and the reverse-transcriptase-associated ribonuclease H (RNH). Hepatitis C virus (HCV) NS5B polymerase shares a similar active site fold to RNH and IN, suggesting that N-hydroxyimides could be useful inhibitor scaffolds of HCV via targeting the NS5B. Herein we describe the design, chemical synthesis, replicon and biochemical assays, and molecular docking of C-6 or C-7 aryl substituted 2-hydroxyisoquinoline-1,3-diones as novel HCV inhibitors. The synthesis involved an improved and clean cyclization method, which allowed the convenient preparation of various analogs. Biological studies revealed that the C-6 analogs, a previously unknown chemotype, consistently inhibit both HCV replicon and recombinant NS5B at low micromolar range. Molecular modeling studies suggest that these inhibitors may bind to the NS5B active site.