title: New 5-benzylidenethiazolidin-4-one inhibitors of bacterial MurD ligase: design, synthesis, crystal structures, and biological evaluation.
abstract: Mur ligases (MurC-MurF), a group of bacterial enzymes that catalyze four consecutive steps in the formation of cytoplasmic peptidoglycan precursor, are becoming increasingly adopted as targets in antibacterial drug design. Based on the crystal structure of MurD cocrystallized with thiazolidine-2,4-dione inhibitor I, we have designed, synthesized, and evaluated a series of improved glutamic acid containing 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD with IC(50) values up to 28 μM. Inhibitor 37, with an IC(50) of 34 μM, displays a weak antibacterial activity against S. aureus ATCC 29213 and E. faecalis ATCC 29212 with minimal inhibitory concentrations of 128 μg/mL. High-resolution crystal structures of MurD in complex with two new inhibitors (compounds 23 and 51) reveal details of their binding modes within the active site and provide valuable information for further structure-based optimization.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Nace
authors.initials: N
authors.lastname: Zidar
authors.forename: Tihomir
authors.initials: T
authors.lastname: Tomašić
authors.forename: Roman
authors.initials: R
authors.lastname: Šink
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovač
authors.forename: Delphine
authors.initials: D
authors.lastname: Patin
authors.forename: Didier
authors.initials: D
authors.lastname: Blanot
authors.forename: Carlos
authors.initials: C
authors.lastname: Contreras-Martel
authors.forename: Andréa
authors.initials: A
authors.lastname: Dessen
authors.forename: Manica Müller
authors.initials: MM
authors.lastname: Premru
authors.forename: Anamarija
authors.initials: A
authors.lastname: Zega
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Lucija Peterlin
authors.initials: LP
authors.lastname: Mašič
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000577:Amides / Q000737:chemistry; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008968:Molecular Conformation; D010453:Peptide Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014498:Uracil / Q000737:chemistry
chemical_list: D000577:Amides; D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D053778:Thiazolidines; D014498:Uracil; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase