Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase.
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.
Zidar
Nace
N
Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia.
Tomasić
Tihomir
T
Sink
Roman
R
Rupnik
Veronika
V
Kovac
Andreja
A
Turk
Samo
S
Patin
Delphine
D
Blanot
Didier
D
Contreras Martel
Carlos
C
Dessen
Andréa
A
Müller Premru
Manica
M
Zega
Anamarija
A
Gobec
Stanislav
S
Peterlin Masic
Lucija
L
Kikelj
Danijel
D
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
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