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

Sara van Poecke (1) , Hélène Munier-Lehmann (2) , Olivier Helynck (2) , Matheus Froeyen (3) , Serge van Calenbergh (1)

1 Laboratory for Medicinal Chemistry-FWW
2 Chimie et Biocatalyse
3 Rega Institute for Medical Research [Leuven, België]

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)=0.17μM). This compound was capable of inhibiting mycobacteria growth at a concentration of 25μg/mL.

Domains: Biochemistry, Molecular Biology

Sara van Poecke, Hélène Munier-Lehmann, Olivier Helynck, Matheus Froeyen, Serge van Calenbergh. Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase.. Bioorganic and Medicinal Chemistry, 2011, 19, epub ahead of print. ⟨10.1016/j.bmc.2011.10.021⟩. ⟨pasteur-00645423⟩