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2-Hydroxy-N-phenylbenzamides and Their Esters Inhibit Acetylcholinesterase and Butyrylcholinesterase

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Abstrakt

The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer's disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman's spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 mu M. IC50 values for BuChE were higher (53.5-228.4 mu M). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine-an established cholinesterases inhibitor used in the treatment of Alzheimer's disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 mu M). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.

Rozsah stran

"698-1"-"698-16"

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2218-273X

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Biomolecules, volume 9, issue: 11

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https://www.mdpi.com/2218-273X/9/11/698

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open access (CC BY 4.0)

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acetylcholinesterase, benzamides, butyrylcholinesterase, enzyme inhibition, esters, in vitro inhibition, phosphorus derivatives, salicylanilides, acetylcholinesteráza, benzamidy, butyrylcholinesteráza, inhibice enzymu, estery, inhibice in vitro, deriváty fosforu, salicylanilidy

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Except where otherwised noted, this item's license is described as open access (CC BY 4.0)