Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N′-thiazol-2-yl-hydrazines

MedChemComm
2019.0

Abstract

Effective treatment of tuberculosis is challenged by the rapid development of <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) 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, <i>N</i>-benzylidene-<i>N</i>'-thiazol-2-yl-hydrazines. Molecular docking of a library of novel <i>N</i>-benzylidene-<i>N</i>'-thiazol-2-yl-hydrazine derivatives into active sites of <i>M. tuberculosis</i> LeuRS (<i>Mtb</i>LeuRS) and MetRS (<i>Mtb</i>MetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against <i>Mtb</i>LeuRS and 28 compounds active against <i>Mtb</i>MetRS. The hit compounds display dual inhibitory potency as demonstrated by IC<sub>50</sub> values for both enzymes. Compound <b>3</b> is active against <i>Mtb</i> H37Rv cells in <i>in vitro</i> bioassays.

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