甲基喹啉酮乙酸类化合物的合成及其 醛糖还原酶抑制活性

目的 合成甲基喹啉酮乙酸类化合物，并评价其对醛糖还原酶的抑制活性。方法 以甲基苯胺为起始原料，经加成、水解、环合、烃化、缩合、水解6步反应得到相应的目标化合物。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醛糖还原酶抑制活性进行初步评价。结果 合成了26个目标化合物，均未见文献报道，目标化合物的结构经核磁共振氢谱和红外光谱确证；6-甲基系列化合物活性均较好，特别是化合物VI ₆（IC₅₀=0.088 μmol.L^-1）活性最好,与依帕司他相当；8-甲基系列化合物活性较弱，只有化合物VI₁₅和VI₂₃活性相对较好，IC₅₀值分别为3.379 、3.055 μmol.L^-1。结论 甲基喹啉酮乙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。

Synthesis and aldose reductase inhibitory activities of methylquinolinoneacetic acids

Aim To synthesize methylquinolinoneacetic acids，and to assay their inhibitory activities against aldose reductase(AR). Methods The methylquinolinoneacetic acids were synthesized via addition, hydrolysis, cyclization, alkylation, condensation, and hydrolysis, a six^-step procedure starting from methyl substituted aniline. Using epalrestat as a control, the aldose reductase inhibitory activities of the compounds obtained were evaluated on rat lens aldose reductase in vitro. Results Twenty^-six compounds were obtained and all of them were not reported yet, and their structures were characterized by ¹H-NMR and IR. Among the compounds tested, 6-methylquinolinoneacetic acids show good activities，and compound VI₆ (IC₅₀=0.088 μmol.L^-1) exhibits the best activity, which is comparable with epalrestat; however, 8- methylquinolinoneacetic acids are relatively weaker, only compounds VI₁₅ and VI₂₃ exert significant activities, the IC₅₀ is 3.379 and 3.055 μmol.L^-1 each. Conclusion The structure-activity relationships of methylquinolinoneacetic acids, as a novel type of aldose reductase inhibitor, should be investigated further.