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Rational Design of 5‘-Thiourea-Substituted α-Thymidine Analogues as Thymidine Monophosphate Kinase Inhibitors Capable of Inhibiting Mycobacterial Growth

2007; American Chemical Society; Volume: 50; Issue: 22 Linguagem: Inglês

10.1021/jm0706158

1520-4804

Ineke Van Daele, Hélène Munier‐Lehmann, Matheus Froeyen, Jan Balzarini, Serge Van Calenbergh,

Biochemical and Molecular Research

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 β-thymidine derivatives inspired us to construct a set of 5'-thiourea-substituted α-thymidine derivatives characterized by a similar relative orientation of the thymine and arylthiourea moieties. α-Thymidine derivative 15, featuring a (3-trifluoromethyl-4-chlorophenyl)thiourea moiety, has a Ki of 0.6 μM 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 μg/mL) and M. tuberculosis (MIC50 = 6.25 μg/mL) strains.