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

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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https://hal-pasteur.archives-ouvertes.fr/pasteur-02892861
Contributor : Hélène Munier-Lehmann <>
Submitted on : Tuesday, July 7, 2020 - 6:30:55 PM
Last modification on : Saturday, July 11, 2020 - 3:45:21 AM

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Yanlin Jian, Fabian Hulpia, Martijn D.P. Risseeuw, He Eun Forbes, Hélène Munier-Lehmann, et al.. Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents. European Journal of Medicinal Chemistry, Elsevier, 2020, 201, pp.112450. ⟨10.1016/j.ejmech.2020.112450⟩. ⟨pasteur-02892861⟩

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