Identification of Novel Aldose Reductase Inhibitors Based on Carboxymethylated Mercaptotriazinoindole Scaffold

Fifteen compounds, sharing an indole-1-acetic acid moiety as a common fragment, were selected from commercial databases for testing aldose reductase inhibition. 3-Mercapto-5H-1,2,4-triazino­[5,6-b]­indole-5-acetic acid (13) was the most promising inhibitor, with an IC50 in the submicromolar range and high selectivity, relative to aldehyde reductase. The crystal structure of aldose reductase complexed with 13 revealed an interaction pattern explaining its high affinity. Physicochemical parameters underline the excellent “leadlikeness” of 13 as a promising candidate for further structure optimizations.本研究从商业数据库中筛选得到15种共享吲哚-1-乙酸（indole-1-acetic acid）共同结构片段的化合物，用于醛糖还原酶（aldose reductase）抑制活性测试。其中3-巯基-5H-1,2,4-三嗪并[5,6-b]吲哚-5-乙酸（13）为最具潜力的抑制剂，其半最大抑制浓度（IC50）处于亚微摩尔级，且相较于醛还原酶（aldehyde reductase）具备优异的选择性。醛糖还原酶与化合物13形成的复合物晶体结构，揭示了其高结合亲和力的相互作用模式。理化参数分析进一步证实，化合物13具备优异的先导化合物类药性（leadlikeness），是后续结构优化的极具潜力的候选化合物。