4-乙氧基酰胺系列化合物的合成及体外活性研究

发布时间：2018-03-18 06:00

本文选题：4-乙氧基　切入点：抗血小板聚集　出处：《天津理工大学》2014年硕士论文　论文类型：学位论文

【摘要】：本课题旨在对计算机辅助药物设计模拟获得的理论结果进行试验验证，以获得新的抗血小板聚集系列创新药物。在实验室前期4-甲氧基-1,3-苯二甲酰胺系列化合物工作基础上，通过计算机辅助药物设计模拟获得的理论结果表明，增大母体苯环4-位取代基的体积，即空阻增加，有利于目标化合物体外抗血小板聚集活性的提高。本文采用4-乙氧基取代前期母体苯环4-甲氧基，研究该基团体积变化后对抗血小板聚集活性的影响。进行了4-乙氧基-1,3-苯二甲酰胺系列目标化合物(PN450-PN464)的设计、合成及部分相关药理试验，所得化合物结构经由MS、IR、1H-NMR光谱表征分析确认，并进行了熔点测定(温度未经校正)。采用Bron比浊法进一步测定了15个目标化合物体外抗ADP诱导的血小板聚集活性，结果显示：其中三个化合物(PN450,PN452,PN454)具有较好的体外抗血小板聚集活性，抑制率高于阳性对照药吡考他胺和阿司匹林；在所有化合物中PN450的IC50值最小，活性远优于两个阳性对照药，PN452的IC50值与对照药相当，两个化合物均具有成为抗血小板聚集备选药物的潜质。对于筛选出体外抗血小板聚集活性较好的化合物PN450,PN452和PN454，以吡考他胺和阿司匹林为对照药，进行了小白鼠急性毒性试验，结果显示三种受试物整体毒性较低，远远低于阿司匹林，与对照药吡考他胺相当。此外，，为了初步了解化合物的细胞毒性，以吡考他胺为对照药，挑选出药理活性和急性毒性结果都比较理想的两个化合物PN450和PN452与L929细胞进行相互作用试验研究。结果显示两个化合物在较高和一般浓度时，对细胞的伤害都较小，与对照药吡考他胺相当。最后，通过分析药理活性数据和化合物结构，对药理活性与侧链苯环取代的构效关系(SAR)进行了推测，为实验室今后的研究工作提供新的数据支持。
[Abstract]:The purpose of this paper is to test and verify the theoretical results of computer aided drug design simulation in order to obtain a series of novel anti-platelet aggregation drugs. The theoretical results obtained by computer aided drug design simulation show that the volume of the 4-position substituents of the benzene ring is increased, that is, the space resistance increases. In order to improve the antiplatelet aggregation activity of target compounds in vitro, 4-ethoxy was used to replace the prophase benzene-4-methoxy group. The effects of the change of the volume of the group on platelet aggregation activity were studied. The design, synthesis and some related pharmacological tests of a series of target compounds (PN450-PN464) were carried out. The structure of the obtained compounds was characterized and confirmed by MS IR 1H-NMR spectroscopy and the melting point was determined (temperature uncorrected). Bron turbidimetric assay was used to further determine the antiplatelet aggregation activity of 15 target compounds induced by ADP in vitro. The results showed that three of them, PN450, PN452PN454) had good antiplatelet aggregation activity in vitro. The inhibitory rate was higher than that of picotadine and aspirin, and the IC50 value of PN450 was the lowest, and the activity of PN452 was much better than that of PN452. Both compounds have the potential to be an alternative to antiplatelet aggregation. For the compounds PN450, PN452 and PN454, which had good antiplatelet aggregation activity in vitro, the acute toxicity tests of mice were carried out with picotadine and aspirin as control drugs. The results showed that the overall toxicity of the three tested compounds was low. Much lower than aspirin, comparable to the control drug picotadine. In addition, in order to understand the cytotoxicity of the compound, picotadine was used as a control drug. Two compounds, PN450 and PN452, which had ideal pharmacological activity and acute toxicity, were selected to study their interaction with L929 cells. The results showed that the two compounds were less harmful to L929 cells at higher and general concentrations. It is comparable to the control drug picotadine. Finally, based on the analysis of the pharmacological activity data and the structure of the compounds, the relationship between pharmacological activity and side chain benzene ring substitution (SAR) was speculated, which provided new data support for the future research work in the laboratory.
【学位授予单位】：天津理工大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R914.5

【相似文献】