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Issue 12, 2019
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Dual-target inhibitors of mycobacterial aminoacyl-tRNA synthetases among N-benzylidene-N′-thiazol-2-yl-hydrazines

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Abstract

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 (MtbLeuRS) and MetRS (MtbMetRS) resulted in a panel of the best ranking compounds, which were then evaluated for enzymatic potency. Screening data revealed 11 compounds active against MtbLeuRS and 28 compounds active against MtbMetRS. The hit compounds display dual inhibitory potency as demonstrated by IC50 values for both enzymes. Compound 3 is active against Mtb H37Rv cells in in vitro bioassays.

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

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Publication details

The article was received on 04 Jul 2019, accepted on 09 Nov 2019 and first published on 28 Nov 2019


Article type: Research Article
DOI: 10.1039/C9MD00347A
Med. Chem. Commun., 2019,10, 2161-2169

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

    O. P. Kovalenko, G. P. Volynets, M. Yu. Rybak, S. A. Starosyla, O. I. Gudzera, S. S. Lukashov, V. G. Bdzhola, S. M. Yarmoluk, H. I. Boshoff and M. A. Tukalo, Med. Chem. Commun., 2019, 10, 2161
    DOI: 10.1039/C9MD00347A

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