Discovery of bicyclic thymidine analogues as selective and high-affinity inhibitors of Mycobacterium tuberculosis thymidine monophosphate kinase.
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.
Vanheusden
Veerle
V
Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, 9000 Ghent, Belgium.
Munier-Lehmann
Hélène
H
Froeyen
Matheus
M
Busson
Roger
R
Rozenski
Jef
J
Herdewijn
Piet
P
Van Calenbergh
Serge
S
D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D008968:Molecular Conformation; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
C494719:1,3-bis((3'-deoxythymidin-3'-yl)methyl)urea; C494718:1-(3-aminomethyl-2-O-,6-N-carbonyl-3-deoxyribofuranosyl)thymine; C494717:1-(3-aminomethyl-3-deoxy-2-O-,6-N-(thiocarbonyl)ribofuranosyl)thymine; D000995:Antitubercular Agents; D014508:Urea; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine