Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages. (14th February 2018)

• Record Type: Journal Article
• 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
• Is Part Of: ChemMedChem. Volume 13:Number 5(2018)
• Page Start: 422
• Page End: 430
• Publication Date: 2018-02-14
• Subjects: 8-hydroxyquinoline-2-hydroxamate -- metalloprotease inhibitors -- Mycobacterium tuberculosis -- QPLD -- Zmp1; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201700759
• Languages: English
• ISSNs: 1860-7179

Abstract

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 of1 c with the zinc ion and residues in the active site. The effect of1 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, inhibitor1 c displays interesting in vitro antitubercular properties worthy of further investigation. Abstract : Expanding the arsenal : Starting from the 8‐hydroxyquinoline privileged structure, we designed a series of inhibitors of the metalloprotease Zmp1. This protease is a virulence factor that allows Mycobaterium tuberculosis to survive inside macrophages. The potent inhibitor1 c is able to impair the growth of M. tuberculosis inside macrophages and is not active against axenic bacteria.