Abstract
We report on Mycobacterium tuberculosis thymidine monophosphate kinase (TMPKmt) inhibitory activities of a series of new 3'- and 5'-modified thymidine analogues including α- and β-derivatives. In addition, several analogues were synthesized in which the 4-oxygen was replaced by a more lipophilic sulfur atom to probe the influence of this modification on TMPKmt inhibitory activity. Several compounds showed an inhibitory potency in the low micromolar range, with the 5'-arylthiourea 4-thio-α-thymidine analogue being the most active one (K(i)=0.17 μM). This compound was capable of inhibiting mycobacteria growth at a concentration of 25 μg/mL.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Humans
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Models, Molecular
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / enzymology*
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Mycobacterium tuberculosis / growth & development
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Nucleoside-Phosphate Kinase / antagonists & inhibitors*
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Nucleoside-Phosphate Kinase / chemistry
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Nucleoside-Phosphate Kinase / metabolism
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Protein Kinase Inhibitors / analogs & derivatives*
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Protein Kinase Inhibitors / chemical synthesis
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Protein Kinase Inhibitors / pharmacology*
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Thymidine / analogs & derivatives*
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Thymidine / chemical synthesis
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Thymidine / pharmacology*
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Thymidine Monophosphate / metabolism
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Tuberculosis / drug therapy
Substances
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Protein Kinase Inhibitors
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Thymidine Monophosphate
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Nucleoside-Phosphate Kinase
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dTMP kinase
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Thymidine