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

Bioorganic & Medicinal Chemistry Letters
Jeong Uk SongGeun Tae Kim

Abstract

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.

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Citations

Nov 15, 2016·Expert Opinion on Therapeutic Patents·Ritu OjhaKunal Nepali
Feb 12, 2019·ChemMedChem·Giuseppe LunaRicardo L Mancera
Nov 14, 2019·International Journal of Molecular Sciences·Rafa S AlmeerHatem K Amin
Nov 5, 2020·Journal of Biomolecular Structure & Dynamics·Khedidja BenarousLuciano Saso
Apr 16, 2021·Oxidative Medicine and Cellular Longevity·Ning LiuWenjie Lu

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