丁苯酞苯环取代衍生物的合成及其抗凝活性研究  

Synthesis and anticoagulant activity of phenyl ring-substituted derivatives of butylphthalide

作　　者：杨娅 贾镇 李毅 李永 汤磊 樊玲玲 YANG Ya;JIA Zhen;LI Yi;LI Yong;TANG Lei;FAN Ling-ling(School of Pharmacy,Guizhou Medical University,Guizhou Province Engineering Technology Research Center for Chemical Drug R&D,Guiyang 550025,China)

机构地区：[1]贵州医科大学药学院,贵州省化学合成药物研发利用工程技术研究中心,贵州贵阳550025

出　　处：《化学研究与应用》2024年第1期111-117,共7页Chemical Research and Application

基　　金：国家自然科学基金项目(32060627)资助;贵州省科技计划项目(黔科合基础-ZK[2023]一般309)资助;贵州省普通高等学校青年科技人才成长计划项目(黔教合KY字[2022] 246号)资助。

摘　　要：为了寻找潜在的治疗缺血性脑卒中候选化合物,以丁苯酞为起始原料,经硝化、还原、酰化、桑德迈尔反应合成了一系列丁苯酞苯环取代衍生物,其结构经~1H-NMR、^(13)C-NMR和HRMS确证。体外抗血小板凝集活性测试结果表明:化合物3、6、8a、8c和9c对二磷酸腺苷(ADP)诱导的血小板凝集的抑制活性(IC_(50)=0.28~0.92 mmol·L^(-1))优于先导化合物丁苯酞(IC_(50)=1.35 mmol·L^(-1))和阳性对照阿司匹林(IC_(50)=1.15 mmol·L^(-1));化合物3、6、8c和9c对花生四烯酸(AA)诱导的血小板凝集具有优良的抑制活性(IC_(50)=0.03~0.15mmol·L^(-1)),其中化合物6(IC_(50)=0.03 mmol·L^(-1))优于阿司匹林(IC_(50)=0.04 mmol·L^(-1))。初步构效关系研究表明在丁苯酞苯环上引入氨基可显著提高其抗血小板凝集活性。In order to find potential candidate compounds for the treatment of ischemic stroke,the butylphthalide was used as a starting material,a series phenyl ring-substituted butylphthalide derivatives were synthesized by nitration,reduction,acylation and Sandmeyer reaction.Their structures were confirmed by ~1H-NMR,^(13)C-NMR and HRMS.The results of antiplatelet agglutination activity test in vitro showed that compounds 3,6,8a,8c and 9c exhibited better inhibitory activity(IC_(50)=0.28-0.92 mmol·L^(-1)) against ADP-induced platelet aggregation than the lead compound butylphthalide(IC_(50)=1.35 mmol·L^(-1)) and positive control aspirin(IC_(50)=1.15 mmol · L^(-1)),compounds 3,6,8c and 9c showed promising inhibitory activity(IC_(50)=0.03~0.15 mmol·L^(-1)) against ADPinduced platelet aggregation,especially compound 6(IC_(50)=0.03 mmol·L^(-1)) was superior to aspirin(IC_(50)=0.04 mmol·L^(-1)).The preliminary structure-activity relationship studies showed that introducing amine groups on the phenyl ring of butylphthalide could significantly enhance its antiplatelet aggregation activity.

关 键 词：丁苯酞衍生物 设计 合成 抗血小板凝集活性 

分 类 号：O625.5[理学—有机化学]