2. Academic Validation
  3. Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents

Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents

  • Eur J Med Chem. 2020 Sep 1;201:112450. doi: 10.1016/j.ejmech.2020.112450.
Yanlin Jian 1,  Fabian Hulpia 1,  Martijn D P Risseeuw 1,  He Eun Forbes 2,  Hélène Munier-Lehmann 3,  Guy Caljon 4,  Helena I M Boshoff 2,  Serge Van Calenbergh 5
Affiliations

Affiliations

  • 1 Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B9000, Gent, Belgium.
  • 2 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.
  • 3 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.
  • 4 Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1(S7), B2610, Wilrijk, Belgium.
  • 5 Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, B9000, Gent, Belgium. Electronic address: [email protected].
PMID: 32623208 DOI: 10.1016/j.ejmech.2020.112450
Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, relies on thymidylate kinase (MtbTMPK) for the synthesis of thymidine triphosphates and thus also DNA synthesis. Therefore, this Enzyme constitutes a potential Achilles heel of the pathogen. Based on a previously reported MtbTMPK 6-aryl-substituted pyridone inhibitor and guided by two co-crystal structures of MtbTMPK with pyridone- and thymine-based inhibitors, we report the synthesis of a series of aryl-shifted cyanopyridone analogues. These compounds generally lacked significant MtbTMPK inhibitory potency, but some analogues did exhibit promising antitubercular activity. Analogue 11i demonstrated a 10-fold increased antitubercular activity (MIC H37Rv, 1.2 μM) compared to literature compound 5. Many analogues with whole-cell antimycobacterial activity were devoid of significant cytotoxicity.

Keywords

Inhibitors; Thymidylate kinase; Tuberculosis.

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