二氢乳清酸脱氢酶抑制剂的设计、合成和构效关系研究

Design,synthesis and structure-activity relationship studies of human dihydroorotate dehydrogenase inhibitors

本文将实验室前期发现的1-丁酰基-3-(4-氯苯基)-5-甲硫基-1H-1,2,4-三氮唑作为人类二氢乳清酸脱氢酶(Hs DHODH)抑制剂设计的苗头化合物,为开展结构优化,首先培养并解析了苗头化合物与Hs DHODH的复合物晶体结构;在此基础上,设计合成了一系列基于苗头结构新颖的Hs DHODH抑制剂。活性结果表明,新合成的目标化合物对Hs DHODH具有较好的抑制活性,其中1-呋喃甲酰基-3-(4-三氟甲基苯基)-5-乙硫基-1H-1,2,4-三氮唑的IC50值达到1.50μmol·L^(-1)。结合生物学活性测试及复合物晶体结构对该系列化合物的构效关系进行了分析与总结,为1H-1,2,4-三氮唑衍生物Hs DHODH抑制剂的进一步优化提供了借鉴经验。

In this study,1-（3-（4-chlorophenyl）-5-methylthio-1H-1,2,4-triazol-1-yl）-butan-1-one discovered previously in our lab was selected as a inhibitor of human dihydroorotate dehydrogenase（Hs DHODH） for structural optimization. The co-crystal of Hs DHODH with the hit was obtained and analyzed for guiding the subsequent structural optimization. As a result,a series of novel triazole derivatives were designed and synthesized as potent Hs DHODH inhibitors. Among them,compound（3-（4-chlorophenyl）-5-ethylthio-1H- 1,2,4-triazol-1-yl）-furan-2-yl-methanone displayed high potency in the inhibition of Hs DHODH with an IC50 value of 1.50 μmol·L^-1. Meanwhile,the structure-activity relationships were analyzed based on the biological data and the co-crystal structure. These results provide a valuable reference for optimization of 1H-1,2,4- triazole derivatives as Hs DHODH inhibitors in the future.