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image of Identification of Novel Dual-targeting Inhibitors of Aminoacyl-tRNA Synthetases in Mycobacterium tuberculosis

Abstract

Introduction

Tuberculosis is a life-threatening infectious disease and a major public health concern. The recent emergence of extensively and totally resistant strains of has driven the search for new antituberculosis agents with previously unexploited mechanisms of action. The main aim of this study is to develop inhibitors with dual-targeted activity toward leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS).

Methods

In order to find LeuRS and MetRS inhibitors, virtual screening was performed with AutoDock software. The top-scoring compounds were then evaluated in aminoacylation assay using radioactive [14C]-L-leucine.

Results

The low molecular weight inhibitors targeting LeuRS were identified among Benzo[b]oxepine-4-carboxylic acid (5-benzyl-thiazol-2-yl)-amide derivatives.

Discussion

The most active compound – 7-Methoxy-benzo[b]oxepine-4-carboxylic acid [5-(2-fluoro-benzyl)-thiazol-2-yl]-amide, inhibited mycobacterial LeuRS with IC value of 19.7 µM. It was found that this compound inhibits MetRS by 96.5% at the concentration of 100 µM. Based on molecular docking results, the compounds from this class bind simultaneously to adenine recognition region and amino acid acceptor region of aminoacyl-tRNA synthetases synthetic sites.

Conclusion

Benzo[b]oxepine-4-carboxylic acid (5-benzyl-thiazol-2-yl)-amide derivatives can be the basis for chemical optimization and biological investigations.

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2025-11-10
2025-12-24

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Identification of Novel Dual-targeting Inhibitors of Aminoacyl-tRNA Synthetases in Mycobacterium tuberculosis
Bentham Science Publishers ; https://doi.org/10.2174/0115734080401691251001061104
/content/journals/cei/10.2174/0115734080401691251001061104
/content/journals/cei/10.2174/0115734080401691251001061104
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  • Article Type:     Letter
Keywords: aminoacylation assay ; Mycobacterium tuberculosis ; inhibitor ; methionyl-tRNA synthetase ; leucyl-tRNA synthetase ; molecular docking

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