Abstract
A series of 5-substituted 2'-deoxyuridine monophosphate analogues has been synthesized and evaluated as potential inhibitors of mycobacterial ThyX, a novel flavin-dependent thymidylate synthase in Mycobacterium tuberculosis. A systematic SAR study led to the identification of compound 5a, displaying an IC(50) value against mycobacterial ThyX of 0.91 μM. This derivative lacks activity against the classical mycobacterial thymidylate synthase ThyA (IC(50) > 50 μM) and represents the first example of a selective mycobacterial FDTS inhibitor.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antitubercular Agents / chemical synthesis*
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Antitubercular Agents / chemistry
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Deoxyuracil Nucleotides / chemical synthesis*
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Deoxyuracil Nucleotides / chemistry
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Deoxyuracil Nucleotides / pharmacology
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Flavins / metabolism*
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Mycobacterium tuberculosis / enzymology*
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Structure-Activity Relationship
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Thymidylate Synthase / antagonists & inhibitors*
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Thymidylate Synthase / chemistry
Substances
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Antitubercular Agents
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Deoxyuracil Nucleotides
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Flavins
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N-(3-(5-(2'-deoxyuridine-5'-monophosphate))prop-2-ynyl)octanamide
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Thymidylate Synthase