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Title: Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages
Authors: Paolino, Marco 
Brindisi, Margherita 
Vallone, Alessandra
Butini, Stefania 
Campiani, Giuseppe 
Nannicini, Chiara
Giuliani, Germano 
Anzini, Maurizio 
Lamponi, Stefania 
Giorgi, Gianluca 
Sbardella, Diego
Ferraris, Davide M
Marini, Stefano
Coletta, Massimo
Palucci, Ivana
Minerva, Mariachiara
Delogu, Giovanni
Pepponi, Ilaria
Goletti, Delia
Cappelli, Andrea 
Gemma, Sandra 
Brogi, Simone
Keywords: 8-hydroxyquinoline-2-hydroxamate; Mycobacterium tuberculosis; QPLD; Zmp1; metalloprotease inhibitors
Issue Date: 2018
Project: None 
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.
ISSN: 1860-7179
DOI: 10.1002/cmdc.201700759
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