Parallel synthesis of 5-cyano-6-aryl-2-thiouracil derivatives as inhibitors for hepatitis C viral NS5B RNA-dependent RNA polymerase

• Published in: Bioorganic chemistry Vol. 34; no. 1; pp. 26 - 38
• Main Authors: Ding, Yili, Girardet, Jean-Luc, Smith, Kenneth L., Larson, Gary, Prigaro, Brett, Wu, Jim Z., Yao, Nanhua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2006
• Subjects: 5-Cyano-6-aryl-2-thiouracil derivatives; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; HCV; Hepacivirus - drug effects; Hepacivirus - enzymology; Humans; Indoles - chemical synthesis; Indoles - metabolism; Inhibitors; Inhibitory Concentration 50; NS5B; Pyridines - chemical synthesis; Pyridines - metabolism; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - metabolism; Structure-Activity Relationship; Uracil - analogs & derivatives; Uracil - chemical synthesis; Uracil - pharmacology; Viral Nonstructural Proteins - genetics; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; 5-Cyano-6-aryl-2-thiouracil derivatives; HCV; Inhibitors; NS5B
• ISSN: 0045-2068; 1090-2120
• DOI: 10.1016/j.bioorg.2005.10.001

Through the parallel synthetic strategy, 5-cyano-6-aryl-2-thiouracilderivatives with single digital micromolar inhibitory activity for the hepatitis C viral NS5B RNA-dependent RNA polymerase were obtained. From random screening of our compound libraries, we identified a hit compound with an IC 50 of 27 μM against hepatitis C viral NS5B RNA-dependent RNA polymerase. By using a parallel synthetic strategy, a series of its derivatives were synthesized. From their anti-HCV activity screening, compounds with single digital 3.8 micromolar activity were obtained.