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

Authors :: Van Poecke S
Munier-Lehmann H
Helynck O
Froeyen M
Van Calenbergh S
Source :: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2011 Dec 15; Vol. 19 (24), pp. 7603-11. Date of Electronic Publication: 2011 Oct 18.
Publication Year :: 2011
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.<br /> (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Subjects :: Humans
Models, Molecular
Mycobacterium tuberculosis growth & development
Nucleoside-Phosphate Kinase chemistry
Nucleoside-Phosphate Kinase metabolism
Protein Kinase Inhibitors chemical synthesis
Thymidine chemical synthesis
Thymidine Monophosphate metabolism
Tuberculosis drug therapy
Mycobacterium tuberculosis drug effects
Mycobacterium tuberculosis enzymology
Nucleoside-Phosphate Kinase antagonists & inhibitors
Protein Kinase Inhibitors analogs & derivatives
Protein Kinase Inhibitors pharmacology
Thymidine analogs & derivatives
Thymidine pharmacology

Full Text Access

Tools