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

Introduction: Tuberculosis is a life-threatening infectious disease and a major public health concern. The recent emergence of extensively and totally resistant strains of Mycobacterium tuberculosis 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 M. tuberculosis leucyl-tRNA synthetase (LeuRS) and methionyl-tRNA synthetase (MetRS). Methods: In order to find M. tuberculosis LeuRS and MetRS inhibitors, virtual screening was performed with AutoDock software. The top-scoring compounds were then evaluated in vitro in aminoacylation assay using radioactive [14C]-L-leucine. Results: The low molecular weight inhibitors targeting M. tuberculosis 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 IC50 value of 19.7 μM. It was found that this compound inhibits M. tuberculosis 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 M. tuberculosis 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.