ChemMedChem · 2018
Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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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
Аннотация
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.