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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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| Authors: | Dr Marco Paolino Dr Margherita Brindisi Dr Alessandra Vallone Prof Stefania Butini Prof Giuseppe Campiani Dr Chiara Nannicini Germano Giuliani Prof Maurizio Anzini Dr Stefania Lamponi Prof Gianluca Giorgi Prof Diego Sbardella Dr Davide M Ferraris Prof Stefano Marini Prof Massimo Coletta Dr Ivana Palucci Dr Mariachiara Minerva Prof Giovanni Delogu Dr Ilaria Pepponi Dr Delia Goletti Prof Andrea Cappelli Sandra Gemma Dr Simone Brogi |
| Affiliation: | 1. European Research Centre for Drug Discovery and Development – NatSynDrugs – and Department of Biotechnology, Chemistry, and Pharmacy, University of Siena, Siena, Italy;2. Department of Clinical Sciences and Translational Medicine, University of Roma Tor Vergata, Rome, Italy;3. Department of Chemical, Food, Pharmaceutical and Pharmacological Sciences, University of Piemonte Orientale “Amedeo Avogadro”, Novara, Italy;4. Institute of Microbiology, Università Cattolica del Sacro Cuore – Fondazione Policlinico Universitario Gemelli, Rome, Italy;5. Translational Research Unit, National Institute for Infectious Diseases (INMI) “L. Spallanzani”, Rome, Italy |
| Abstract: | 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. |
| Keywords: | 8-hydroxyquinoline-2-hydroxamate metalloprotease inhibitors Mycobacterium tuberculosis QPLD Zmp1 |
