Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages

Marco Paolino, Margherita Brindisi, Alessandra Vallone, Stefania Butini, Giuseppe Campiani, Chiara Nannicini, Germano Giuliani, Maurizio Anzini, Stefania Lamponi, Gianluca Giorgi, Diego Sbardella, Davide M. Ferraris, Stefano Marini, Massimo Coletta, Ivana Palucci, Mariachiara Minerva, Giovanni Delogu, Ilaria Pepponi, Delia Goletti, Andrea CappelliSandra Gemma, Simone Brogi

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)422-430
Number of pages9
JournalChemMedChem
Volume13
Issue number5
DOIs
Publication statusPublished - Mar 6 2018

Keywords

  • 8-hydroxyquinoline-2-hydroxamate
  • metalloprotease inhibitors
  • Mycobacterium tuberculosis
  • QPLD
  • Zmp1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Pharmacology, Toxicology and Pharmaceutics(all)
  • Organic Chemistry

Fingerprint Dive into the research topics of 'Development of Potent Inhibitors of the Mycobacterium tuberculosis Virulence Factor Zmp1 and Evaluation of Their Effect on Mycobacterial Survival inside Macrophages'. Together they form a unique fingerprint.

Cite this