吡嗪类化合物的合成及其抗血小板凝集活性测试

为提高川芎嗪的抗血小板凝集活性,分别以不同的二胺、2,3-丁二酮和硫辛酸为起始原料,采用溴代、水解、环化、氧化、氢化、取代等反应,通过四条路线合成了7个川芎嗪衍生物,其结构经1H NMR、13C NMR及ESI-MS确证。采用Born比浊法初步测试了化合物的体外抗血小板凝集活性,结果显示,化合物1(IC50=0. 26mmol/L)、2(IC50=0. 27mmol/L)和7(IC50=0. 21mmol/L)对由二磷酸腺苷(ADP)诱导的血小板凝集具有一定的抑制活性,优于先导化合物川芎嗪(IC50=0. 49mmol/L)。因此,在不改变川芎嗪药效团的前提下对其进行不同程度的环化,能明显提高川芎嗪的抗血小板凝集活性,此研究为后期化合物的结构修饰提供了一定的参考价值。

Synthesis and Anti-platelet Aggregation Activity Evaluation of Pyrazines

In order to improve the antiplatelet agglutination activity of ligustrazine, different diamines, 2,3-butanedione and lipoic acid were used as starting materials, seven new ligustrazine derivatives were synthesized via four routes, including bromination, hydrolysis, cyclization, oxidation, hydrogenation and substitution reaction. The structures were confirmed by 1HNMR, 13CNMR and ESI-MS, and their in vitro anti-platelet aggregation activity have been tested preliminarily by the Born turbidimetric method. The experimental results showed that compounds 1 (IC50 = 0.26 mmol/L), 2 (IC50 = 0.27mmol/L) and 7 (IC50 = 0.21mmol/L) exhibited significant inhibitory activity for adenosine diphosphate (ADP) induced platelet aggregation comparison with the lead compound ligustrazine (IC50 = 0.49mmol/L). Therefore, without changing ligustrazine pharmacophore, cyclization in different degree can obviously improve the antiplatelet agglutination activity of ligustrazine, which has useful reference value for the structure modification of lead compound.