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.
© 2018 Deutsche Pharmazeutische Gesellschaft.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / chemistry
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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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Bacterial Proteins / antagonists & inhibitors*
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Bacterial Proteins / chemistry
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Escherichia coli / drug effects
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Heterocyclic Compounds / chemical synthesis*
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Heterocyclic Compounds / chemistry
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Heterocyclic Compounds / pharmacology
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Inhibitory Concentration 50
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Microbial Sensitivity Tests
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Molecular Structure
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Staphylococcus aureus / drug effects
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Structure-Activity Relationship
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Heterocyclic Compounds
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Alkyl and Aryl Transferases
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UDP-N-acetylglucosamine 1-carboxyvinyltransferase