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Title: Rational design of 5'-thiourea-substituted alpha-thymidine analogues as thymidine monophosphate kinase inhibitors capable of inhibiting mycobacterial growth
Authors: Van Daele, Ineke ×
Munier-Lehmann, Hélène
Froeyen, Mathy
Balzarini, Jan
Van Calenbergh, Serge #
Issue Date: Nov-2007
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:50 issue:22 pages:5281-5292
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.
URI: 
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
Medicinal Chemistry (Rega Institute)
× corresponding author
# (joint) last author

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