摘要
目的为寻找抗血小板聚集活性更高的药物,参照吡考他胺的构效关系和贝曲西班的官能团特征,设计并合成9个未见文献报道的3-芳酰氨基-4-甲氧基苯甲酰胺类化合物。方法以3-硝基-4-甲氧基苯甲酸为起始原料,与二氯亚砜反应制得中间体3-硝基-4-甲氧基苯甲酰氯,该中间体与不同取代基的苯胺反应生成3-硝基-4-甲氧基苯甲酰胺类化合物,将该类化合物中的硝基分别还原为氨基,然后与4-甲氧基苯甲酰氯反应制得目标化合物4a-4i。目标化合物的结构经1H-NMR、13C-NMR和ESI-MS谱确证。以阿司匹林和吡考他胺为阳性对照药,ADP为诱导剂,采用Born比浊法对目标化合物进行体外抗血小板聚集活性评价;再根据体外抗血小板聚集活性结果,采用CCK-8法对活性较好的目标化合物进行体外细胞毒性测试。结果与结论药理活性实验结果表明,在130μmol·L-1浓度下,4个化合物4a、4c、4g、4i的抗血小板聚集活性优于阳性对照药吡考他胺,其中化合物4c的活性最高。细胞毒性实验结果表明,在10μmol·L-1浓度下,待测化合物几乎没有明显的细胞毒性。构效关系表明,在侧链苯环邻位或对位引入氟原子或溴原子获得的化合物的活性较高。
In order to discover drugs with higher anti-platelet aggregation activities,referring to the structureactivity relationship of picotamide and the functional group characteristics of betrixaban,nine 3-arylamino-4-methoxybenzamides which were not reported in literature were designed and synthesized.Used 3-nitro-4-methoxybenzoic acid as the starting material,the intermediate 3-nitro-4-methoxybenzoyl chloride was synthesized by reacting with thionyl chloride.The intermediate reacted with different substituted anilines to give 3-nitro-4-methoxybenzamides.The nitro group of compounds was reducted to amino group,and then reacted with 4-methoxybenzoylchloride to obtain target compounds 4a-4i.The structures of the target compounds were characterized by 1H-NMR,13 C-NMR and ESI-MS.Using aspirin and pictotamide as the positive control drugs,the in vitro anti-platelet aggregation activities of the target compounds were evaluated by Born′s test induced by adenosine diphosphate(ADP).Moreover,according to the results of in vitro antiplatelet aggregation activity,compounds with higher activities were chosen to further conduct in vitro cytotoxicity study by cell counting Kit-8(CCK-8)assays.Pharmacological experiment results revealed that under the concentration of 1.30μmol·L-1,four compounds 4a,4c,4g and 4i exhibited higher anti-platelet aggregation activities than picotamide,among them,compound 4c had the highest activity.Cyototoxicity experiment results showed that under the concentration of 10μmol·L-1,tested compounds have no obvious cytotoxicities.What′s more,structure-activity relationship showed that the compounds bearing fluorine or bromine at o-or p-position of the side chain benzene rings had higher anti-platelet activity ■ .
作者
陈馨
李彩文
李贵良
赵东亚
刘秀杰
CHEN Xin;LI Cai⁃wen;LI Gui⁃liang;ZHAO Dong⁃ya;LIU Xiu⁃jie(Tianjin Key Laboratory of Drag Targeting and Bioimaging,Tianjin 300384,China;Tianjin Key Laboratory of Organic Solar Cells and Photochemical Conversion,Tianjin University of Technology,Tianjin 300384,China;Department of Pharmaceutical Engineering,School of Chemistry and Chemical Engineering,Tianjin University of Technology,Tianjin 300384,China)
出处
《中国药物化学杂志》
CAS
CSCD
北大核心
2020年第3期136-141,共6页
Chinese Journal of Medicinal Chemistry
基金
国家自然科学基金资助项目(11341014)
天津市自然科学基金重点项目(15JCZDJC33100)
