title: Novel 2-thioxothiazolidin-4-one inhibitors of bacterial MurD ligase targeting D-Glu- and diphosphate-binding sites.
abstract: Mur ligases are involved in cytoplasmic steps of bacterial peptidoglycan biosynthesis and are viable targets for antibacterial drug discovery. We have designed and synthesized a focused chemical library of compounds combining the glutamic acid moiety and the 2-thioxothiazolidin-4-one, thiazolidine-2,4-dione, 2-iminothiazolidin-4-one or imidazolidine-2,4-dione ring connected by a benzylidene group. These compounds were designed to target the d-Glu- and the diphosphate-binding pockets of the MurD active site and were evaluated for inhibition of MurD ligase from Escherichia coli. The most potent compounds (R)-9 and (S)-9 inhibited MurD with IC(50) values of 45 μM and 10 μM, respectively. The specific binding mode of (R)-9 in MurD active site was established by high-resolution NMR spectroscopy.
authors.affiliation: University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia.
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašić
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovač
authors.forename: Mihael
authors.initials: M
authors.lastname: Simčič
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Simona Golič
authors.initials: SG
authors.lastname: Grdadolnik
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
authors.forename: Lucija
authors.initials: L
authors.lastname: Peterlin Mašič
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D053778:Thiazolidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D053778:Thiazolidines; C033089:thiazoline-2-thione; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase