Discovery and structure–activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 6; pp. 1581 - 1588
• Main Authors: Wang, Ning-Yu, Zuo, Wei-Qiong, Xu, Ying, Gao, Chao, Zeng, Xiu-Xiu, Zhang, Li-Dan, You, Xin-Yu, Peng, Cui-Ting, Shen, Yang, Yang, Sheng-Yong, Wei, Yu-Quan, Yu, Luo-Ting
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-03-2014
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Cell Line; Cell Survival - drug effects; Drug Evaluation, Preclinical; HEK293 Cells; Hepacivirus - drug effects; Hepatitis C virus; Hepatitis C virus (HCV); Humans; Pyridines - chemical synthesis; Pyridines - chemistry; Pyridines - pharmacology; Pyridines - toxicity; Structure activity relationship (SAR); Structure-Activity Relationship; Thieno[2,3-b]pyridine; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Virus Replication - drug effects; Structure activity relationship (SAR); Hepatitis C virus (HCV); Thieno[2,3-b]pyridine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.01.075

SAR investigation on five regions of thieno[2,3-b]pyridine derivatives led to the discovery of several promising compounds which exhibited low micromolar potency against HCV replicon.
Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50=3.3μM, SI >30.3, 12b, EC50=3.5μM, SI >28.6, 10l, EC50=3.9μM, SI >25.6, 12o, EC50=4.5μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.