Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

Veerle Vanheusden; Hélène Munier-Lehmann; Matheus Froeyen; Roger Busson; Jef Rozenski; Piet Herdewijn; Serge Van Calenbergh

doi:10.1021/jm040847w

Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase

J Med Chem. 2004 Dec 2;47(25):6187-94. doi: 10.1021/jm040847w.

Authors

Veerle Vanheusden¹, Hélène Munier-Lehmann, Matheus Froeyen, Roger Busson, Jef Rozenski, Piet Herdewijn, Serge Van Calenbergh

Affiliation

¹ Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.

PMID: 15566289
DOI: 10.1021/jm040847w

Abstract

Thymidine monophosphate kinase of Mycobacterium tuberculosis (TMPKmt) represents an attractive target for selectively blocking bacterial DNA synthesis. Hereby, we report on the discovery of a novel class of bicyclic nucleosides (10 and 11) and one dinucleoside (12), belonging to the most selective inhibitors of TMPKmt discovered so far.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antitubercular Agents / chemical synthesis*
Antitubercular Agents / pharmacology
Crystallography, X-Ray
Models, Molecular
Molecular Conformation
Mycobacterium tuberculosis / drug effects*
Mycobacterium tuberculosis / enzymology
Nucleoside-Phosphate Kinase / antagonists & inhibitors*
Nucleoside-Phosphate Kinase / chemistry
Protein Binding
Structure-Activity Relationship
Thymidine / analogs & derivatives*
Thymidine / chemical synthesis*
Thymidine / pharmacology
Urea / analogs & derivatives*
Urea / chemical synthesis*
Urea / pharmacology

Substances

1,3-bis((3'-deoxythymidin-3'-yl)methyl)urea
1-(3-aminomethyl-2-O-,6-N-carbonyl-3-deoxyribofuranosyl)thymine
1-(3-aminomethyl-3-deoxy-2-O-,6-N-(thiocarbonyl)ribofuranosyl)thymine
Antitubercular Agents
Urea
Nucleoside-Phosphate Kinase
dTMP kinase
Thymidine