Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors
Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors
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DOI：
10.1016/j.bmcl.2015.12.055
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发表时间：
2016-02-01
影响因子：
2.7
通讯作者：
Kim, Geun Tae
中科院分区：
文献类型：
--
作者：
Song, Jeong Uk;Jang, Jae Wan;Kim, Geun Tae
抑制黄嘌呤氧化酶（XO）显然是控制高尿酸血症的核心概念，高尿酸血症导致严重和痛苦的炎症性关节炎疾病，如痛风。我们发现了一系列新的2-（吲哚-2-基）噻唑衍生物在纳米摩尔活性水平上作为XO抑制剂。利用分子建模程序（Accelrys Software program）进行结构导向设计，为2-（吲哚-2-基）噻唑类化合物的优化提供了良好的基础。构效关系表明，吲哚环上5位疏水性烷氧基（异丙氧基、环戊氧基）和7位氢键受体（NO2、CN）是关键官能团。其中，2-（7-硝基-5-异丙氧基-吲哚-2-基）-4-甲基噻唑-5-羧酸（9m）在氧酸钾诱导的高尿酸血症大鼠模型中表现出最强的XO抑制活性（IC50值：5.1 nM）和优异的降尿酸活性。(C) 2016年Elsevier Ltd.出版
Inhibition of xanthine oxidase (XO) has obviously been a central concept for controlling hyperuricemia, which causes serious and painful inflammatory arthritis disease such as gout. We discovered a series of novel 2-(indol-2-yl) thiazole derivatives as XO inhibitors at the level of nanomolar activity. Structure-guided design using molecular modeling program (Accelrys Software program) provided an excellent basis for optimization of 2-(indol-2-yl) thiazole compounds. Structure-activity relationship indicated that hydrophobic alkoxy group (isopropoxy, cyclopentoxy) at 5-position and hydrogen binding acceptor (NO2, CN) at 7-position of indole ring appear as critical functional groups. Among the compounds, 2-(7-nitro-5-isopropoxy- indol-2-yl)-4-methylthiazole-5-carboxylic acid (9m) exhibits the most potent XO inhibitory activity (IC50 value: 5.1 nM) and the excellent uric acid lowering activity in potassium oxonate induced hyperuricemic rat model. (C) 2016 Published by Elsevier Ltd.