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

Authors
  • Jian, Yanlin
  • Hulpia, Fabian
  • Risseeuw, Martijn
  • Forbes, He Eun
  • Munier-Lehmann, Hélène
  • Caljon, Guy
  • Boshoff, Helena I. M.
  • Van Calenbergh, Serge
Publication Date
Jan 01, 2020
Identifiers
DOI: 10.1016/j.ejmech.2020.112450
OAI: oai:archive.ugent.be:8664899
Source
Ghent University Institutional Archive
Keywords
Language
English
License
White
External links

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.

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