1. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.
- Author
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Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Lukashov SS, Kovalenko OP, Kriklivyi IA, Yaremchuk AD, Starosyla SA, Yarmoluk SM, and Tukalo MA
- Subjects
- Amino Acid Sequence, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology, Humans, Leucine-tRNA Ligase chemistry, Leucine-tRNA Ligase metabolism, Models, Molecular, Molecular Sequence Data, Mycobacterium tuberculosis chemistry, Nitrophenols chemical synthesis, Nitrophenols chemistry, Nitrophenols pharmacology, Protein Structure, Tertiary, Sequence Alignment, Tuberculosis microbiology, Antitubercular Agents chemistry, Antitubercular Agents pharmacology, Leucine-tRNA Ligase antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Tuberculosis drug therapy
- Abstract
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. Leucyl-tRNA 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 6μM. 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 2.27μM. 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=10.01μM and IC90=13.53μM., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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