α-苯亚甲基-β-氧代苯丙酸衍生物的合成及其醛糖还原酶抑制活性

Synthesis and aldose reductase inhibitory activity of α-(phenylmethylene)-β-oxo-benzenepropanoic acid derivatives

目的设计合成新的α-苯亚甲基-β-氧代苯丙酸类化合物,并评价其对醛糖还原酶的抑制活性。方法根据具有醛糖还原酶抑制活性的查尔酮类天然产物的基本结构及醛糖还原酶抑制剂的作用机制,设计了一系列α-苯亚甲基-β-氧代苯丙酸类化合物,并以取代苯乙酮为起始原料,经3步反应得到目标产物。以依帕司他为阳性对照药,采用大鼠晶状体醛糖还原酶对目标化合物的醛糖还原酶抑制活性进行初步评价。结果合成了14个目标化合物,其中12个未见文献报道,结构经核磁共振氢谱和红外光谱确证。在浓度为1×10-4mol.L-1时,化合物9显示出较好活性,抑制率为80.48%。结论α-苯亚甲基-β-氧代苯丙酸类化合物作为新型醛糖还原酶抑制剂,其构效关系值得进一步研究。

Aim To design and synthesize novel α-（phenylmethylene）-β-oxo-benzenepropanoic acid derivatives , and to assay their inhibitory activity against aldose reductase（AR）. Methods Based on the general structure of chalcone-type compounds having aldose reductase inhibitory activity and the molecular action mechanism of known aldose reductase inhibitors（ARIs）, α-（phenylmethylene）-β-oxo-benzenepropanoic acid derivatives were designed , and the target compounds were synthesized via a three-step procedure starting from substituted acetophenones. Using epalrestat as a control, the aldose reductase inhibitory activity of the compounds obtained was evaluated on rat lens aldose reductase in vitro. Results Fourteen compounds were obtained and twelve of them were not reported in the literature, and their structures were characterized by ^1H-NMR and IR. Among the compounds tested, compound 9 shows an inhibitory rate of 80.48 96 under the concentration of 1×10^-4mol·L^-1. Conclusion The structure-activity relationships of α- （phenylmethylene）- β-oxo-benzenepropanoic acid derivatives as a novel type of aldose reductase inhibitor should be investigated further.