Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among <i>N</i>-benzylidene-<i>N</i>'-thiazol-2-yl-hydrazines

Effective treatment of tuberculosis is challenged by the rapid development of Mycobacterium tuberculosis ( Mtb ) multidrug resistance that presumably could be overcome with novel multi-target drugs. Aminoacyl-tRNA synthetases (AARSs) are an essential part of protein biosynthesis machinery and attractive targets for drug discovery. Here, we experimentally verify a hypothesis of simultaneous targeting of structurally related AARSs by a single inhibitor. We previously identified a new class of mycobacterial leucyl-tRNA synthetase inhibitors, N -benzylidene- N '-thiazol-2-yl-hydrazines. Molecular docking of a library of novel N -benzylidene- N '-thiazol-2-yl-hydrazine derivatives into active sites of M. tuberculosis LeuRS ( Mtb LeuRS) and MetRS ( Mtb MetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against Mtb LeuRS and 28 compounds active against Mtb MetRS. The hit compounds display dual inhibitory potency as demonstrated by IC 50 values for both enzymes. Compound 3 is active against Mtb H37Rv cells in in vitro bioassays.