Bromo-cyclobutenaminones as new covalent udp-n-acetylglucosamine enolpyruvyl transferase (Mura) inhibitors

David J. Hamilton, Péter Ábrányi-Balogh, Aaron Keeley, László Petri, Martina Hrast, Tímea Imre, Maikel Wijtmans, Stanislav Gobec, Iwan J.P. de Esch, György Miklós Keserű*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Drug discovery programs against the antibacterial target UDP-N-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small threeand five-membered heterocyclic rings. In the current study, the reactivity of four-membered rings was carefully modulated to obtain a novel family of covalent MurA inhibitors. Screening a small library of cyclobutenone derivatives led to the identification of bromo-cyclobutenaminones as new electrophilic warheads. The electrophilic reactivity and cysteine specificity have been determined in a glutathione (GSH) and an oligopeptide assay, respectively. Investigating the structure-activity relationship for MurA suggests a crucial role for the bromine atom in the ligand. In addition, MS/MS experiments have proven the covalent labelling of MurA at Cys115 and the observed loss of the bromine atom suggests a net nucleophilic substitution as the covalent reaction. This new set of compounds might be considered as a viable chemical starting point for the discovery of new MurA inhibitors.

Original languageEnglish
Article number362
Pages (from-to)1-14
Number of pages14
JournalPharmaceuticals
Volume13
Issue number11
Early online date3 Nov 2020
DOIs
Publication statusPublished - Nov 2020

Bibliographical note

Special Issue: Novel Antibacterial Agents.

Keywords

  • Antibacterial
  • Covalent inhibitor
  • Cyclobutenaminone
  • Irreversible
  • MurA

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