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

• Published in: Chinese chemical letters Vol. 27; no. 7; pp. 1052 - 1057
• Main Authors: Tang, Sheng, Peng, Zong-Gen, Zhang, Xin, Cheng, Xin-Yue, Li, Wen-Jing, Jiang, Jian-Dong, Li, Ying-Hong, Song, Dan-Qing
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.07.2016
• Subjects: EC50值; HCV; Hepatitis C virus; Matrinic acid; Matrinic amide; Structure–activity relationship; 合成; 家庭; 生物学评价; 苯; 药物; 酰胺衍生物; Matrinic acid; Hepatitis C virus; Matrinic amide; Structure–activity relationship
• ISSN: 1001-8417; 1878-5964
• DOI: 10.1016/j.cclet.2016.03.006

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.