Structure-based design and biological evaluation of novel 2-(indol-2-yl) thiazole derivatives as xanthine oxidase inhibitors

被引：42

作者：

Song, Jeong Uk ^{[1
,2
]}

Jang, Jae Wan ^{[2
]}

Kim, Tae Hun ^{[2
]}

Park, Heuisul ^{[2
]}

Park, Wan Su ^{[2
]}

Jung, Sang-Hun ^{[1
]}

Kim, Geun Tae ^{[2
]}

机构：

[1] Chungnam Natl Univ, Coll Pharm, Daejeon 305764, South Korea

[2] LG Life Sci Ltd, Res & Dev, 188 Munji Ro, Daejeon 305380, South Korea

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2016年 / 26卷 / 03期

关键词：

Xanthine oxidase inhibitors; Hyperuricemia; Molecular modeling; Structure-activity relationship; 2-(Indol-2-yl) thiazole; OXIDASE/XANTHINE-DEHYDROGENASE; METABOLIC SYNDROME; CRYSTAL-STRUCTURE; HYPERURICEMIA; GOUT; OXIDOREDUCTASE; MANAGEMENT; DISCOVERY; ACID; OPTIMIZATION;

D O I：

10.1016/j.bmcl.2015.12.055

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：950 / 954

页数：5

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