Bromo-Cyclobutenaminones as New Covalent UDP-<i>N</i>-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors

• Main Authors: David J. Hamilton (Author), Péter Ábrányi-Balogh (Author), Aaron Keeley (Author), László Petri (Author), Martina Hrast (Author), Tímea Imre (Author), Maikel Wijtmans (Author), Stanislav Gobec (Author), Iwan J. P. de Esch (Author), György Miklós Keserű (Author)
• Format: Book
• Published: MDPI AG, 2020-11-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

Drug discovery programs against the antibacterial target UDP-<i>N</i>-acetylglucosamine enolpyruvyl transferase (MurA) have already resulted in covalent inhibitors having small three- and 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.

Item Description

10.3390/ph13110362
1424-8247