Bromo-Cyclobutenaminones as New Covalent UDP-N-Acetylglucosamine Enolpyruvyl Transferase (MurA) Inhibitors
David J. Hamilton, Péter Ábrányi‐Balogh, Aaron Keeley, László Petri, Martina Hrast, Tı́mea Imre, Maikel Wijtmans, Stanislav Gobec, Iwan J. P. de Esch, György M. Keserű
Abstract
-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.