新型2-苯基苯并呋喃-3-酰胺衍生物的设计、合成及对Sortase A的抑制活性  

Design,Synthesis and Sortase A Inhibitory Activity of Novel 2-Phenyl-benzofuran-3-amide Derivatives

作　　者：胡杨 姜发琴[1] 张勇[2] 张东东 傅磊[1] HU Yang;JIANG Faqin;ZHANG Yong;ZHANG Dongdong;FU Lei(Shanghai Key Lab.for Molecular Engineering of Chiral Drugs,School of Pharmacy,Shanghai Jiao Tong University,Shanghai 200240;School of Life Sciences and Biotechnology,Shanghai Jiao Tong University,Shanghai 200240)

机构地区：[1]上海交通大学药学院,上海市手性药物分子工程重点实验室,上海200240 [2]上海交通大学生命科学技术学院,上海200240

出　　处：《中国医药工业杂志》2020年第3期371-380,共10页Chinese Journal of Pharmaceuticals

摘　　要：以金黄色葡萄球菌转肽酶Sortase A与底物LPXTG的结合构象为模板,设计合成了12个具有L-shape构象的2-苯基苯并呋喃-3-酰胺衍生物作为Sortase A抑制剂,并经核磁共振和高分辨质谱确认结构,其中10个目标化合物未见文献报道。体外抑制活性结果显示,9个目标化合物对Sortase A具有较好的抑制活性[IC50=(22.2~62.3)μmol/L]。构效关系分析结果表明,苯并呋喃3-位上的取代基为-CONHCH2CH(CH3)2时抑制活性较好,而为-COOH时则抑制活性丧失;2-位苄基上带有吸电子基如氰基时抑制活性较好,而为供电子基如羟基时抑制活性较差;苯并呋喃其他位置上的取代基对抑制活性未见明显影响。Based on the binding conformation of Staphylococcus aureus transpeptidase Sortase A and the substrate LPXTG as a template,twelve 2-phenyl-benzofuran-3-amide derivatives with L-shape conformation were designed and synthesized.The structures were confirmed by NMR and high-resolution mass spectrometry,and among them,ten target compounds had not been reported in the literature.Nine compounds showed excellent in vitro inhibitory activities on Sortase A[IC50=(22.2-62.3)μmol/L].The structure-activity relationship analysis revealed that the inhibitory activity was better when-CONHCH2CH(CH3)2 at the 3-position of benzofuran,while the inhibitory activity was lost when-COOH at the same position,when the 2-position benzyl group had an electron withdrawing group such as cyano,the inhibitory activity was improved,compared with the electron donor group,such as-OH,the substituents at other positions of benzofuran had no significant effect on the inhibitory activity.

关 键 词：分选酶A 设计与合成 苯并呋喃衍生物 构效关系分析 

分 类 号：R914.4[医药卫生—药物化学]