Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase

J Med Chem. 2010 Sep 23;53(18):6584-94. doi: 10.1021/jm100285g.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Catalytic Domain
  • Crystallography, X-Ray
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Glutamic Acid / analogs & derivatives*
  • Glutamic Acid / chemical synthesis
  • Glutamic Acid / chemistry
  • Glutamic Acid / pharmacology
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Models, Molecular
  • Molecular Structure
  • Peptide Synthases / antagonists & inhibitors*
  • Protein Binding
  • Rhodanine / analogs & derivatives*
  • Rhodanine / chemical synthesis*
  • Rhodanine / chemistry
  • Rhodanine / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiazolidinediones / chemical synthesis*
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology
  • Thiazolidines / chemical synthesis*
  • Thiazolidines / chemistry
  • Thiazolidines / pharmacology

Substances

  • 2-(3-((4-((2,4-dioxothiazolidin-5-ylidene)methyl)phenylamino)methyl)benzamido)pentanedioic acid
  • Anti-Bacterial Agents
  • Escherichia coli Proteins
  • Thiazolidinediones
  • Thiazolidines
  • Glutamic Acid
  • Rhodanine
  • Peptide Synthases
  • UDP-N-acetylmuramoylalanine-D-glutamate ligase

Associated data

  • PDB/2X5O