5-Benzylidenethiazolidin-4-ones as Multitarget Inhibitors of Bacterial Mur Ligases.
ChemMedChem 2009 Dec 18; In press
Tomašić T, Zidar N, Kovač A, Turk S, Simčič M, Blanot D, Müller-Premru M, Filipič M, Grdadolnik S SG, Zega A, Anderluh M, Gobec S, Kikelj D, Peterlin Mašič L
University of Ljubljana, Faculty of Pharmacy, Askerceva 7, 1000 Ljubljana (Slovenia), Fax: (+386) 1-425-8031.
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 mum, 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.
Keywords: Mur Ligase