含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂的合成及其构效关系

摘要

分别以1-溴萘和酮或1-萘甲醛及有机金属试剂为原料,经12步反应合成了8个含萘三氮唑甲烷骨架的硫代乙酸类尿酸转运体1(URAT1)抑制剂(1h～1o),其结构经1H NMR,13C NMR和MS (ESI)表征.体外活性测试结果显示:对URAT1的抑制活性最强的是1k,是阳性对照药lesinurad的133倍[IC50=0.054 μmol·L-1(1k),7.18 μmol·L-1(lesinurad)].%Eight naphthyltriazolylmethane-based thioacetic acids(1h ～ 1o) were synthesized as uric acid transporter 1 (URAT1) inhibitors by 12 steps using 1-bromonaphthalene and ketones or 1-naphth-aldehyde and alkyl organometallic reagents as starting materials.The structures were characterized by 1H NMR,13C NMR and MS(ESI).In vitro URAT1 inhibitory assay showed that 1k was the most potent URAT1 inhibitor among target compounds,which was 133-fold more potent than positive control lesinurad(IC5o =0.054 μmol · L-1 for 1k against human URAT1 vs 7.18 μmol · L-1 for lesinurad).