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

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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
Organic Chemistry, Pharmacology, Drug Discovery, General Medicine

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MLA
Jian, Yanlin, et al. “Synthesis and Structure Activity Relationships of Cyanopyridone Based Anti-Tuberculosis Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 201, 2020, doi:10.1016/j.ejmech.2020.112450.
APA
Jian, Y., Hulpia, F., Risseeuw, M., Forbes, H. E., Munier-Lehmann, H., Caljon, G., … Van Calenbergh, S. (2020). Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 201. https://doi.org/10.1016/j.ejmech.2020.112450
Chicago author-date
Jian, Yanlin, Fabian Hulpia, Martijn Risseeuw, He Eun Forbes, Hélène Munier-Lehmann, Guy Caljon, Helena I. M. Boshoff, and Serge Van Calenbergh. 2020. “Synthesis and Structure Activity Relationships of Cyanopyridone Based Anti-Tuberculosis Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 201. https://doi.org/10.1016/j.ejmech.2020.112450.
Chicago author-date (all authors)
Jian, Yanlin, Fabian Hulpia, Martijn Risseeuw, He Eun Forbes, Hélène Munier-Lehmann, Guy Caljon, Helena I. M. Boshoff, and Serge Van Calenbergh. 2020. “Synthesis and Structure Activity Relationships of Cyanopyridone Based Anti-Tuberculosis Agents.” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 201. doi:10.1016/j.ejmech.2020.112450.
Vancouver
1.
Jian Y, Hulpia F, Risseeuw M, Forbes HE, Munier-Lehmann H, Caljon G, et al. Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. 2020;201.
IEEE
[1]
Y. Jian et al., “Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents,” EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 201, 2020.
@article{8664899,
  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.}},
  articleno    = {{112450}},
  author       = {{Jian, Yanlin and Hulpia, Fabian and Risseeuw, Martijn and Forbes, He Eun and Munier-Lehmann, Hélène and Caljon, Guy and Boshoff, Helena I. M. and Van Calenbergh, Serge}},
  issn         = {{0223-5234}},
  journal      = {{EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}},
  keywords     = {{Organic Chemistry,Pharmacology,Drug Discovery,General Medicine}},
  language     = {{eng}},
  pages        = {{15}},
  title        = {{Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents}},
  url          = {{http://dx.doi.org/10.1016/j.ejmech.2020.112450}},
  volume       = {{201}},
  year         = {{2020}},
}

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