Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase
Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase
复制标题
DOI：
10.1016/j.bmc.2016.01.028
复制
发表时间：
2016-03-01
影响因子：
3.5
通讯作者：
Tukalo, Michail A.
中科院分区：
文献类型：
--
作者：
Gudzera, Olga I.;Golub, Andriy G.;Tukalo, Michail A.
结核病是由人类病原菌结核分枝杆菌引起的一种严重传染病。细菌耐药性是当今医学上的一个重要问题，开发具有不同作用机制的新型抗生素是现代医学的重要目标。亮氨酰t-RNA合成酶（LeuRS）是近年来临床验证的抗菌靶标。在这里，我们报告的发现，小分子抑制剂的M。结核病LeuRS。使用基于受体的虚拟筛选，我们已经确定了六个抑制剂的M。结核病LeuRS来自两种不同的化学类别。活性最强的化合物4-{[4-（4-溴-苯基）-噻唑-2-基]肼基甲基}-2-甲氧基-6-硝基-苯酚（1）抑制LeuRS，IC 50为6 μ M。合成了一系列衍生物并进行了体外抗M.结核病LeuRS。结果表明，活性最强的化合物2，6-二溴-4 {[4-（4-硝基-苯基）-噻唑-2-基]-肼基甲基}-苯酚抑制LeuRS，IC 50为2.27 μ M。测试所有活性化合物对M.结核病H37 Rv.化合物1似乎具有最好的细胞渗透性，并抑制病原菌的生长，IC 50 = 10.01 μ M和IC 90 = 13.53 μ M。(C)2016爱思唯尔有限公司版权所有
Tuberculosis is a serious infectious disease caused by human pathogen bacteria Mycobacterium tuberculosis. Bacterial drug resistance is a very significant medical problem nowadays and development of novel antibiotics with different mechanisms of action is an important goal of modern medical science. Leucylt-RNA synthetase (LeuRS) has been recently clinically validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors of M. tuberculosis LeuRS. Using receptor-based virtual screening we have identified six inhibitors of M. tuberculosis LeuRS from two different chemical classes. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl] hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 of 6 mu M. A series of derivatives has been synthesized and evaluated in vitro toward M. tuberculosis LeuRS. It was revealed that the most active compound 2,6-Dibromo-4{[4-(4-nitro-phenyl)-thiazol-2-yl]-hydrazonomethyl}-phenol inhibits LeuRS with IC50 of 2.27 mu M. All active compounds were tested for antimicrobial effect against M. tuberculosis H37Rv. The compound 1 seems to have the best cell permeability and inhibits growth of pathogenic bacteria with IC50 = 10.01 mu M and IC90 = 13.53 mu M. (C) 2016 Elsevier Ltd. All rights reserved.