2. Academic Validation
  3. Novel thiazolidinedione-hydroxamates as inhibitors of Mycobacterium tuberculosis virulence factor Zmp1

Novel thiazolidinedione-hydroxamates as inhibitors of Mycobacterium tuberculosis virulence factor Zmp1

  • Eur J Med Chem. 2020 Jan 1:185:111812. doi: 10.1016/j.ejmech.2019.111812.
Veronika Šlachtová 1,  Marek Šebela 2,  Eveline Torfs 3,  Lauren Oorts 3,  Davie Cappoen 3,  Karel Berka 4,  Václav Bazgier 4,  Lucie Brulíková 5
Affiliations

Affiliations

  • 1 Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46, Olomouc, Czech Republic.
  • 2 Department of Protein Biochemistry and Proteomics, Centre of the Region Haná for Biotechnological and Agricultural Research, Faculty of Science, Palacký University, Šlechtitelů 27, 783 71, Olomouc, Czech Republic.
  • 3 Laboratory of Microbiology, Parasitology and Hygiene (LMPH), S7, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.
  • 4 Department of Physical Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacky University, 17. listopadu 12, 771 46, Olomouc, Czech Republic.
  • 5 Department of Organic Chemistry, Faculty of Science, Palacký University, 17. listopadu 12, 771 46, Olomouc, Czech Republic. Electronic address: lucie.brulikova@upol.cz.
PMID: 31703818 DOI: 10.1016/j.ejmech.2019.111812
Abstract

Zinc metalloprotease 1 (Zmp1) is an extracellular Enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS. Nine of the tested compounds were found to inhibit the enzymatic reaction more effectively than the generic metalloprotease inhibitor phosphoramidon. Furthermore, the synthesized thiazolidinedione-hydroxamate hybrids were evaluated for their in vitro antimycobacterial activity and acute cytotoxicity using whole-cell assays. Results showed that none of the hybrids exhibited acute cytotoxicity against RAW264.7 macrophages. Whereas extracellular antimycobacterial activity was limited, RAW264.7 macrophage Infection results showed that a majority of the hybrids inhibited the intracellular growth of Mycobacterium tuberculosis at a concentration of 100 and 10 μM. The thiazolidinedione-hydroxamate compound 2n was considered to be the best candidate of the evaluated library.

Keywords

Hydroxamates; MALDI-TOF; Mycobacterium tuberculosis; Thiazolidinediones; Zmp1.

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