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

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Jian, Yanlin | Hulpia, Fabian | Risseeuw, Martijn D.P. | Forbes, He Eun | Munier-Lehmann, Hélène | Caljon, Guy | Boshoff, Helena I.M. | van Calenbergh, Serge

Edité par CCSD ; Elsevier -

International audience. 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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