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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.

SUBMITTER: Jian Y

PROVIDER: S-EPMC8362676 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Jian Yanlin Y Hulpia Fabian F Risseeuw Martijn D P MDP Forbes He Eun HE Munier-Lehmann Hélène H Caljon Guy G Boshoff Helena I M HIM Van Calenbergh Serge S

European journal of medicinal chemistry 20200612

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 analo ...[more]

PMID: 32623208

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