Synthesis and biological evaluation of 12-benzyl matrinic amide derivatives as a novel family of anti-HCV agents  

作　　者：Sheng Tang Zong-Gen Peng Xin Zhang Xin-Yue Cheng Wen-Jing Li Jian-Dong Jiang Ying-Hong Li Dan-Qing Song 

机构地区：[1]Beijing Key Laboratory of Anti-infective Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College

出　　处：《Chinese Chemical Letters》2016年第7期1052-1057,共6页中国化学快报（英文版）

基　　金：supported by the National Natural Science Foundation of China (Nos. 21472246 and 81321004);the Beijing Natural Science Foundation (No. 7152097);National Mega-Project for Innovation Drugs (No. 2012ZX09103101-037)

摘　　要：A new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized from matrinine（1）and evaluated for their anti-HCV activity,taking compound 2 as the lead.SAR revealed that the introduction of a suitable substituent at the N’-end of matrinic amide might greatly enhance the potency.Among them,matrinic acid 17 and N’-substituted matrinic amides 18a-d exhibited promising potency with low micromolar EC50 values ranging from 1.03μmol/L to 7.54 μmol/L,and better therapeutic window with SI from 66 to 132.Moreover,compound 17 displayed an excellent PK and safety profile in vivo,demonstrating good drug-like characteristics.Thus,it has been selected for further investigation,with an advantage of decreased chances of inducing drug-resistance mutations.A new series of 12-benzyl matrinic amide/ethanamide derivatives were synthesized from matrinine（1）and evaluated for their anti-HCV activity,taking compound 2 as the lead.SAR revealed that the introduction of a suitable substituent at the N’-end of matrinic amide might greatly enhance the potency.Among them,matrinic acid 17 and N’-substituted matrinic amides 18a-d exhibited promising potency with low micromolar EC50 values ranging from 1.03μmol/L to 7.54 μmol/L,and better therapeutic window with SI from 66 to 132.Moreover,compound 17 displayed an excellent PK and safety profile in vivo,demonstrating good drug-like characteristics.Thus,it has been selected for further investigation,with an advantage of decreased chances of inducing drug-resistance mutations.

关 键 词：Matrinic acid Matrinic amide Hepatitis C virus Structure–activity relationship 

分 类 号：O621.3[理学—有机化学] TQ460.1[理学—化学]