1. Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase.
- Author
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Gudzera, Olga I., Golub, Andriy G., Bdzhola, Volodymyr G., Volynets, Galyna P., Lukashov, Sergiy S., Kovalenko, Oksana P., Kriklivyi, Ivan A., Yaremchuk, Anna D., Starosyla, Sergiy A., Yarmoluk, Sergiy M., and Tukalo, Michail A.
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ANTITUBERCULAR agents , *TARGETED drug delivery , *LEUCYL-tRNA synthetase , *TUBERCULOSIS treatment , *DRUG resistance , *DRUG development - 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 IC 50 of 6 μM. 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 IC 50 of 2.27 μM. 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 IC 50 = 10.01 μM and IC 90 = 13.53 μM. [ABSTRACT FROM AUTHOR]
- Published
- 2016
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