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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Catalytic Domain
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Crystallography, X-Ray
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Escherichia coli Proteins / antagonists & inhibitors*
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Glutamic Acid / analogs & derivatives*
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Glutamic Acid / chemical synthesis
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Glutamic Acid / chemistry
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Glutamic Acid / pharmacology
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Gram-Negative Bacteria / drug effects
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Gram-Positive Bacteria / drug effects
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Models, Molecular
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Molecular Structure
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Peptide Synthases / antagonists & inhibitors*
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Protein Binding
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Rhodanine / analogs & derivatives*
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Rhodanine / chemical synthesis*
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Rhodanine / chemistry
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Rhodanine / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Thiazolidinediones / chemical synthesis*
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Thiazolidinediones / chemistry
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Thiazolidinediones / pharmacology
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Thiazolidines / chemical synthesis*
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Thiazolidines / chemistry
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Thiazolidines / pharmacology
Substances
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2-(3-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)methyl)benzamido)pentanedioic acid
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Anti-Bacterial Agents
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Escherichia coli Proteins
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Thiazolidinediones
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Thiazolidines
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Glutamic Acid
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Rhodanine
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Peptide Synthases
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UDP-N-acetylmuramoylalanine-D-glutamate ligase