期刊
PHARMACEUTICALS
卷 13, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ph13110362
关键词
covalent inhibitor; MurA; cyclobutenaminone; antibacterial; irreversible
资金
- H2020 MSCA FragNet [675899]
- SNN [125496]
- OTKA [PD124598, 2018-2.1.11-TET-SI-2018-00005]
- Slovenian Research Agency [P1-0208]
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.
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