title: Rational design of 5'-thiourea-substituted alpha-thymidine analogues as thymidine monophosphate kinase inhibitors capable of inhibiting mycobacterial growth.
abstract: Recently, thymidine monophosphate kinase (TMPK) emerged as an attractive target for developing inhibitors of Mycobacterium tuberculosis growth. The elucidation of the X-ray structure of TMPK of M. tuberculosis (TMPKmt), as well as the structure of an earlier serendipitously discovered dimeric thymidine inhibitor, laid the foundation for the design of potent and selective TMPKmt inhibitors reported here. Several hits identified within a series of 3'-C-branched thiourea-substituted beta-thymidine derivatives inspired us to construct a set of 5'-thiourea-substituted alpha-thymidine derivatives characterized by a similar relative orientation of the thymine and arylthiourea moieties. alpha-Thymidine derivative 15, featuring a (3-trifluoromethyl-4-chlorophenyl)thiourea moiety, has a Ki of 0.6 microM and a selectivity index of 600 versus human TMPK. Moreover, it represents the first TMPK inhibitor showing good inhibitory activity on growing M. bovis (MIC99 = 20 microg/mL) and M. tuberculosis (MIC50 = 6.25 microg/mL) strains.
authors.affiliation: Laboratory for Medicinal Chemistry (FFW), University of Gent, Harelbekestraat 72, 9000 Ghent, Belgium.
authors.forename: Ineke
authors.initials: I
authors.lastname: Van Daele
authors.forename: Hélène
authors.initials: H
authors.lastname: Munier-Lehmann
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D019281:Dimerization; D006801:Humans; D008958:Models, Molecular; D009161:Mycobacterium / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D009163:Mycobacterium bovis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D009705:Nucleosides; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013890:Thiourea; D013936:Thymidine