title: Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase.
abstract: We have designed, synthesized, and evaluated 5-benzylidenerhodanine- and 5-benzylidenethiazolidine-2,4-dione-based compounds as inhibitors of bacterial enzyme MurD with E. coli IC(50) in the range 45-206 μM. The high-resolution crystal structure of MurD in complex with (R,Z)-2-(3-[{4-([2,4-dioxothiazolidin-5-ylidene]methyl)phenylamino}methyl)benzamido)pentanedioic acid [(R)-32] revealed details of the binding mode of the inhibitor within the active site and provides a good foundation for structure-based design of a novel generation of MurD inhibitors.
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: Tomasić
authors.forename: Roman
authors.initials: R
authors.lastname: Sink
authors.forename: Veronika
authors.initials: V
authors.lastname: Rupnik
authors.forename: Andreja
authors.initials: A
authors.lastname: Kovac
authors.forename: Samo
authors.initials: S
authors.lastname: Turk
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
authors.initials: M
authors.lastname: Müller Premru
authors.forename: Anamarija
authors.initials: A
authors.lastname: Zega
authors.forename: Stanislav
authors.initials: S
authors.lastname: Gobec
authors.forename: Lucija
authors.initials: L
authors.lastname: Peterlin Masic
authors.forename: Danijel
authors.initials: D
authors.lastname: Kikelj
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D010453:Peptide Synthases / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C552701:2-(3-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)methyl)benzamido)pentanedioic acid; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D045162:Thiazolidinediones; D053778:Thiazolidines; D018698:Glutamic Acid; D012236:Rhodanine; D010453:Peptide Synthases; C053379:UDP-N-acetylmuramoylalanine-D-glutamate ligase