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Title
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Synthesis and structure activity relationships of cyanopyridone based anti-tuberculosis agents
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Author
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Abstract
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| 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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Language
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English
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Source (journal)
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European journal of medicinal chemistry. - Paris, 1974, currens
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Publication
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Paris
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2020
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ISSN
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0223-5234
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DOI
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10.1016/J.EJMECH.2020.112450
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Volume/pages
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201
(2020)
, p. 1-15
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Article Reference
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112450
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ISI
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000556579600018
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Pubmed ID
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32623208
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Medium
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E-only publicatie
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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