Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 244, Issue -, Pages -Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2022.114831
Keywords
Mycobacterium tuberculosis; Virulence factor Zmp1; Hydroxamate; Thiazolidinedione; Indole; Pyrrole
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Funding
- Palacky University in Olomouc [JG_2019_002]
- Research Foundation - Flanders [G066619N]
- ELIXIR CZ research infrastructure project [LM2018131]
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This paper examines the inhibitory effect of thiazolidinediones 2 on the intracellular survival of Mycobacterium tuberculosis. The most active derivative 2f showed a significant reduction of bacterial survival within the macrophage host cell. These findings suggest that thiazolidinediones 2 have the potential to be used as Zmp1 inhibitors for the treatment of tuberculosis.
Mycobacterial zinc metalloprotease-1 (Zmp1) is an essential enzyme for intracellular survival and pathogenicity of Mycobacterium tuberculosis. However, the exact mechanism of function of this enzyme remains unclear. This paper examines the effect of novel organic molecules on the inhibition of Zmp1. We followed our previous results and synthesised three libraries of new hydroxamates. All compounds were studied for their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis by MALDI-TOF MS. Furthermore, a macrophage infection assay was performed to evaluate intracellular antimycobacterial activity. In the whole-cell assay, no direct activity of synthesised heterocyclic hydroxamates was observed against Mycobacterium tuberculosis and Mycobacterium bovis. No acute cellular toxicity was observed against the murine RAW 264.7 macrophage cell line and human MRC-5 lung fibroblast cell line. However, thiazolidinediones 2 showed the dose-dependent inhibition of intracellular survival of Mycobacterium tuberculosis H37Ra. The inhibition was structure-dependent, with the most active derivative 2f inducing an 83.2% reduction of bacterial survival within the macrophage host cell. The promising biological activity confirmed thiazolidinediones 2 as Zmp1 inhibitors that can be used as tool compounds for further exploration of the role of Zmp1 for in vivo pathogenicity. In the long run, thiazolidinediones 2 show the potential to act as a scaffold for Zmp1 inhibitors to target intracellular Mtb as a novel tuberculosis treatment strategy.
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