title: Synthesis and inhibitory activity of thymidine analogues targeting Mycobacterium tuberculosis thymidine monophosphate kinase.
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.
authors: Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
authors: Sara
authors: S
authors: Van Poecke
authors: Hélène
authors: H
authors: Munier-Lehmann
authors: Olivier
authors: O
authors: Helynck
authors: Matheus
authors: M
authors: Froeyen
authors: Serge
authors: S
authors: Van Calenbergh
mesh_terms: D006801:Humans; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013938:Thymidine Monophosphate / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D047428:Protein Kinase Inhibitors; D013938:Thymidine Monophosphate; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine