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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 antibiotics with novel mechanisms of action is an important goal of modern medical science. Leucyl-tRNA synthetase (LeuRS) has been already validated as antimicrobial target. Here we report the discovery of small-molecule inhibitors for mycobacterial LeuRS. Using receptor-based virtual screening we have identified four inhibitors of M. tuberculosis LeuRS among the derivatives of N-Benzylidene-N'-thiazol-2-yl-hydrazine. The most active compound 4-{[4-(4-Bromo-phenyl)-thiazol-2-yl]hydrazonomethyl}-2-methoxy-6-nitro-phenol (1) inhibits LeuRS with IC50 value 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 IC50 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 IC50 = 10.01 μM and IC90 = 13.53 μM.

antitb1 s
Figure 1. The binding mode of compound 1 in the active site of LeuRS M. tuberculosis. Hydrogen bonds are shown by the dotted lines.

  • Discovery of potent anti-tuberculosis agents targeting leucyl-tRNA synthetase. Gudzera OI, Golub AG, Bdzhola VG, Volynets GP, Lukashov SS, Kovalenko OP, Kriklivyi IA, Yaremchuk AD, Starosyla SA, Yarmoluk SM, Tukalo MA. Bioorg Med Chem. 2016, 24(5): 1023-1031. 
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