Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages
© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim..
The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:13 |
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| Enthalten in: |
ChemMedChem - 13(2018), 5 vom: 06. März, Seite 422-430 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Paolino, Marco [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 04.03.2019 Date Revised 04.03.2019 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/cmdc.201700759 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279966873 |
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| 245 | 1 | 0 | |a Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages |
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| 520 | |a © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a The enzyme Zmp1 is a zinc-containing peptidase that plays a critical role in the pathogenicity of Mycobacterium tuberculosis. Herein we describe the identification of a small set of Zmp1 inhibitors based on a novel 8-hydroxyquinoline-2-hydroxamate scaffold. Among the synthesized compounds, N-(benzyloxy)-8-hydroxyquinoline-2-carboxamide (1 c) was found to be the most potent Zmp1 inhibitor known to date, and its binding mode was analyzed both by kinetics studies and molecular modeling, identifying critical interactions of 1 c with the zinc ion and residues in the active site. The effect of 1 c on intracellular Mycobacterium survival was assayed in J774 murine macrophages infected with M. tuberculosis H37Rv or M. bovis BCG and human monocyte-derived macrophages infected with M. tuberculosis H37Rv. Cytotoxicity and genotoxicity were also assessed. Overall, inhibitor 1 c displays interesting in vitro antitubercular properties worthy of further investigation | ||
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| 650 | 4 | |a Mycobacterium tuberculosis | |
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| 650 | 4 | |a metalloprotease inhibitors | |
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| 650 | 7 | |a Zmp1 protein, Mycobacterium tuberculosis |2 NLM | |
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| 700 | 1 | |a Butini, Stefania |e verfasserin |4 aut | |
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| 700 | 1 | |a Lamponi, Stefania |e verfasserin |4 aut | |
| 700 | 1 | |a Giorgi, Gianluca |e verfasserin |4 aut | |
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