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 Keserü M. (Author)

Abstract

Drug discovery programs against the antibacterial target UDP-N-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.

Keywords

covalent inhibitor;MurA;cyclobutenaminone;antibacterial;irreversible;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL FFA - Faculty of Pharmacy
UDC: 615.4:54
COBISS: 46907907 Link will open in a new window
ISSN: 1424-8247
Views: 128
Downloads: 64
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Other data

Secondary language: Slovenian
Secondary keywords: zaviralci MurA;antibakterijske učinkovine;Zdravila;Farmacevtska kemija;
Type (COBISS): Article
Pages: str. 1-14
Volume: ǂVol. ǂ13
Issue: ǂiss. ǂ11
Chronology: 2020
DOI: 10.3390/ph13110362
ID: 14373095