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Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function

Identifikátory výsledku

  • Kód výsledku v 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>

  • Výsledek na webu

    <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>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function

  • Popis výsledku v původním jazyce

    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.

  • Název v anglickém jazyce

    Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function

  • Popis výsledku anglicky

    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.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    10401 - Organic chemistry

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/LM2018131" target="_blank" >LM2018131: Česká národní infrastruktura pro biologická data</a><br>

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Ostatní

  • Rok uplatnění

    2022

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

  • ISSN

    0223-5234

  • e-ISSN

    1768-3254

  • Svazek periodika

    244

  • Číslo periodika v rámci svazku

    DEC

  • Stát vydavatele periodika

    FR - Francouzská republika

  • Počet stran výsledku

    15

  • Strana od-do

    "114831-1 "-"114831-15"

  • Kód UT WoS článku

    000869783500004

  • EID výsledku v databázi Scopus

    2-s2.0-85139735634