2-(2-乙基-5-氟苯并呋喃-3-甲酰胺基)-4-甲基噻唑-5-羧酸的合成及活性  

Synthesis and activity of 2-(2-ethyl-5-fluorobenzofuran-3-carboxamido)-4-methylthiazole-5-carboxylic acid

作　　者：谢珺 苗菁 崔杏 王建塔 王聪 汤磊 XIE Jun;MIAO Jing;CUI Xing;WANG Jianta;WANG Cong;TANG Lei(School of Pharmacy,Guizhou Medical University,Guiyang 550025,Guizhou,China;Guizhou Provincial Engineering Technology Research Center for Chemical Drug R&D,Guiyang 550004,Guizhou,China)

机构地区：[1]贵州医科大学药学院,贵州贵阳550025 [2]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550004

出　　处：《贵州医科大学学报》2023年第11期1307-1314,共8页Journal of Guizhou Medical University

基　　金：化学药仿创技术应用国家地方联合工程技术研究中心(2019);贵州省常见重大慢性疾病发病机制及药物开发应用创新基地(黔科中引地〔2021〕4029);2023年度贵州省卫生健康委科学技术基金(gzwkj2023-232)。

摘　　要：目的探讨噻唑类衍生物的合成及黄嘌呤氧化酶(XO)活性的测定。方法以苯并呋喃羧酸为原料,合成噻唑类衍生物;以非布索坦作为阳性对照,目标化合物3a~3d,6a~6d作为实验组,以20μmol/L为起始浓度,采用尿酸法检测XO的活性,采用分子对接预测化合物与靶蛋白的结合方式。结果合成了3a~3d和6a~6d共8个噻唑类化合物;优化了羧基和氨基缩合合成酰胺的条件,用二环已基碳二亚胺做缩合剂、二氯甲烷做溶剂、反应4 h收率最高;用氢核磁共振(^(1)H NMR)、碳核磁共振(^(13)C NMR)及电喷雾电离质谱(ESI-MS)数据确认目标化合物,且在20μmol/L、40μmol/L及80μmol/L浓度下均对XO都有一定的抑制活性;分子对接的结果酰胺直接连接噻唑环和苯并呋喃环的化合物与XO的相互作用和非布索坦相似。结论化合物6d对XO具有较好的抑制活性。Objective To explore the synthesis of thiazole derivatives and the determination of xanthine oxidase(XO)activity.Methods Thiazole derivatives were synthesized from benzofuran carboxylic acid.Febuxostm was used as a positive control,and the target compounds 3a-3d and 6a-6d were used as experimental groups.The activity of XO was detected by the uric acid method using 20μmol/L as the starting concentration,and molecular docking was used to predict the binding mode of the compound and the target protein.Results A total of 8 thiazoles were synthesized from 3a-3d and 6a-6d.The conditions for the condensation of the carboxyl and amino groups were optimized.Dicyclic carbon diimide was used as condensate,dichlorylene as solvent,and the reaction 4 h yield was the highest.The target compounds were confirmed with hydrogen NMR(^(1)H NMR),carbon NMR(^(13)C NMR),and electrospray ionization mass spectrometry(ESI-MS)data,and it showed some inhibitory activity on XO at concentration of 20μmol/L,40μmol/L,and 80μmol/L.The molecular docking results suggested that the compounds of the amide directly connecting the thiazole ring to the benzofuran ring interacted similarly with XO and nonbuxostat.Conclusion Compound 6d has a better inhibitory activity against XO.

关 键 词：非布索坦 黄嘌呤氧化酶 设计 合成 活性 分子对接 

分 类 号：R914.5[医药卫生—药物化学]