Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15310%2F22%3A73615705" target="_blank" >RIV/61989592:15310/22:73615705 - isvavai.cz</a>
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0223523422007334" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523422007334</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.ejmech.2022.114831" target="_blank" >10.1016/j.ejmech.2022.114831</a>
Alternative languages
Result language
angličtina
Original language name
Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10401 - Organic chemistry
Result continuities
Project
<a href="/en/project/LM2018131" target="_blank" >LM2018131: Czech National Infrastructure for Biological Data</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2022
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0223-5234
e-ISSN
1768-3254
Volume of the periodical
244
Issue of the periodical within the volume
DEC
Country of publishing house
FR - FRANCE
Number of pages
15
Pages from-to
"114831-1 "-"114831-15"
UT code for WoS article
000869783500004
EID of the result in the Scopus database
2-s2.0-85139735634