Bioorganic & Medicinal Chemistry 2011-12-15

Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase

Sara Van Poecke, Hélène Munier-Lehmann, Olivier Helynck, Matheus Froeyen, Serge Van Calenbergh

文献索引：Bioorg. Med. Chem. 19(24) , 7603-1, (2011)

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摘要

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.