2. Academic Validation
  3. Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

Endeavors towards transformation of M. tuberculosis thymidylate kinase (MtbTMPK) inhibitors into potential antimycobacterial agents

  • Eur J Med Chem. 2020 Nov 15;206:112659. doi: 10.1016/j.ejmech.2020.112659.
Yanlin Jian 1,  Romain Merceron 2,  Steven De Munck 2,  He Eun Forbes 3,  Fabian Hulpia 1,  Martijn D P Risseeuw 1,  Kristof Van Hecke 4,  Savvas N Savvides 2,  Hélène Munier-Lehmann 5,  Helena I M Boshoff 3,  Serge Van Calenbergh 6
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium.
  • 2 VIB Center for Inflammation Research, Zwijnaarde, Ghent, 9052, Belgium; Department of Biochemistry and Microbiology, Ghent University, Ghent, 9052, Belgium.
  • 3 Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Disease, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, United States.
  • 4 XStruct, Department of Chemistry, Ghent University, Krijgslaan 281 S3, Gent, B-9000, Belgium.
  • 5 Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, Institut Pasteur, CNRS UMR3523, 28 Rue du Dr. Roux, Cedex, 15 75724, Paris, France.
  • 6 Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium. Electronic address: serge.vancalenbergh@ugent.be.
PMID: 32823003 DOI: 10.1016/j.ejmech.2020.112659
Abstract

As the last Enzyme in nucleotide synthesis as precursors for DNA replication, thymidylate kinase of M. tuberculosis (MtbTMPK) attracts significant interest as a target in the discovery of new anti-tuberculosis agents. Earlier, we discovered potent MtbTMPK inhibitors, but these generally suffered from poor antimycobacterial activity, which we hypothesize is due to poor Bacterial uptake. To address this, we herein describe our efforts to equip previously reported MtbTMPK inhibitors with targeting moieties to increase the whole cell activity of the hybrid analogues. Introduction of a simplified Fe-chelating siderophore motif gave rise to analogue 17 that combined favorable Enzyme inhibitory activity with significant activity against M. tuberculosis (MIC of 12.5 μM). Conjugation of MtbTMPK inhibitors with an imidazo[1,2-a]pyridine or 3,5-dinitrobenzamide scaffold afforded analogues 26, 27 and 28, with moderate MtbTMPK Enzyme inhibitory potency, but sub-micromolar activity against mycobacteria without significant cytotoxicity. These results indicate that conjugation with structural motifs known to favor mycobacterial uptake may be a valid approach for discovering new antimycobacterial agents.

Keywords

Antimycobacterial; Mycobacteria tuberculosis; Siderophore; Thymidine monophosphate kinase (TMPK); Uptake.

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