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• W4313255416 endingPage "115048" @default.
• W4313255416 startingPage "115048" @default.
• W4313255416 abstract "Alongside reversible butyrylcholinesterase inhibitors, a plethora of covalent butyrylcholinesterase inhibitors have been reported in the literature, typically pseudo-irreversible carbamates. For these latter, however, most cases lack full confirmation of their covalent mode of action. Additionally, the available reports regarding the structure-activity relationships of the O-arylcarbamate warhead are incomplete. Therefore, a follow-up on a series of pseudo-irreversible covalent carbamate human butyrylcholinesterase inhibitors and the structure-activity relationships of the N-dialkyl O-arylcarbamate warhead are presented in this study. The covalent mechanism of binding was tested by IC50 time-dependency profiles, and sequentially and increasingly confirmed by kinetic analysis, whole protein LC-MS, and crystallographic analysis. Computational studies provided valuable insights into steric constraints and identified problematic, bulky carbamate warheads that cannot reach and carbamoylate the catalytic Ser198. Quantum mechanical calculations provided further evidence that steric effects appear to be a key factor in determining the covalent binding behaviour of these carbamate cholinesterase inhibitors and their duration of action. Additionally, the introduction of a clickable terminal alkyne moiety into one of the carbamate N-substituents and in situ derivatisation with azide-containing fluorophore enabled fluorescent labelling of plasma human butyrylcholinesterase. This proof-of-concept study highlights the potential of this novel approach and for these compounds to be further developed as clickable molecular probes for investigating tissue localisation and activity of cholinesterases." @default.
• W4313255416 created "2023-01-06" @default.
• W4313255416 creator A5005346086 @default.
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• W4313255416 creator A5080573224 @default.
• W4313255416 creator A5081384764 @default.
• W4313255416 creator A5081592140 @default.
• W4313255416 date "2023-02-01" @default.
• W4313255416 modified "2023-10-18" @default.
• W4313255416 title "Pseudo-irreversible butyrylcholinesterase inhibitors: Structure–activity relationships, computational and crystallographic study of the N-dialkyl O-arylcarbamate warhead" @default.
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