基于喹喔啉酮结构的醛糖还原酶抑制剂的设计合成与构效关系研究

Design,Synthesis and StructureActivity Relationship Study of Aldose Reductase Inhibitors Based on Quinoxalinone Structure

本文以喹喔啉酮为母核结构,在其N1位引入羧基,同时对C3位侧链结构进行优化,设计合成了一系列喹喔啉酮衍生物作为醛糖还原酶抑制剂候选物.活性检测结果表明,所有化合物均显示出明显的醛糖还原酶抑制活性.其中,2-(3-(4-羟基苯丙烯基)-2-氧喹喔啉-1(2H)-烷基)乙酸(4d)展现出最强的抑制活性,IC50值为93 nmol/L,与目前上市的epalrestat活性相当(IC50=83 nmol/L).另外,分子对接研究表明化合物4d与醛糖还原酶的活性位点结合比较紧密.

A series of aldose reductase(ALR2)inhibitor candidates were designed and synthesized based on quinoxalin-2(1H)-one,and a carboxyl group was introduced at N1 position.Moreover,the side chain at C3 position was modified.All compounds were tested for ALR2 inhibitory activity,showing significant inhibition.The results also show that,among them,2-(3-(4-hydroxyphenylpropenyl)-2-oxoquinoxaline-1(2H)-alkyl)acetic acid(4d)demonstrate the most potent inhibitory activity with an IC50 value of 93 nmol/L,being equal to epalrestat(IC50=83 nmol/L),which is the only commercial aldose reductase inhibitor(ARI).In addition,molecular docking experiments reveal that compound 4d can bind tightly to the active site of aldose reductase.