Heterocyclic electrophiles as new MurA inhibitors

Arch Pharm (Weinheim). 2018 Dec;351(12):e1800184. doi: 10.1002/ardp.201800184. Epub 2018 Nov 21.

Abstract

An electrophilic fragment library of small heterocycles was developed and characterized in the surrogate GSH-reactivity assay and aqueous stability test that revealed their potential as covalent warheads. Screening the library against MurA from Staphylococcus aureus (MurASA ) and Escherichia coli (MurAEC ) identified heterocyclic fragments with significant inhibitory potency. The validated heterocyclic warhead library might be useful for developing targeted covalent inhibitors for other targets of interest with a new design strategy incorporating heterocyclic electrophiles as warheads.

Keywords: MurA inhibitor; electrophilic fragment; fragment-based drug discovery; heterocycle.

MeSH terms

  • Alkyl and Aryl Transferases / antagonists & inhibitors*
  • Alkyl and Aryl Transferases / chemistry
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / chemistry
  • Escherichia coli / drug effects
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology
  • Inhibitory Concentration 50
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Heterocyclic Compounds
  • Alkyl and Aryl Transferases
  • UDP-N-acetylglucosamine 1-carboxyvinyltransferase