5-Benzylidenethiazolidin-4-ones as multitarget inhibitors of bacterial Mur ligases.
Mur ligases participate in the intracellular path of bacterial peptidoglycan biosynthesis and constitute attractive, although so far underexploited, targets for antibacterial drug discovery. A series of hydroxy-substituted 5-benzylidenethiazolidin-4-ones were synthesized and tested as inhibitors of Mur ligases. The most potent compound 5 a was active against MurD-F with IC(50) values between 2 and 6 microm, making it a promising multitarget inhibitor of Mur ligases. Antibacterial activity against different strains, inhibitory activity against protein kinases, mutagenicity and genotoxicity of 5 a were also investigated, and kinetic and NMR studies were conducted.
Tomasić
Tihomir
T
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana, Slovenia.
Zidar
Nace
N
Kovac
Andreja
A
Turk
Samo
S
Simcic
Mihael
M
Blanot
Didier
D
Müller-Premru
Manica
M
Filipic
Metka
M
Grdadolnik
Simona Golic
SG
Zega
Anamarija
A
Anderluh
Marko
M
Gobec
Stanislav
S
Kikelj
Danijel
D
Peterlin Masic
Lucija
L
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020552:Comet Assay; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase