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

Martin Krátký,Rudolf Vosátka,Šárka Štěpánková,Katarína Vorčáková,Neto-Honorius Houngbedji,Jarmila Vinšová

doi:10.3390/biom9110698

Abstract

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 µM. IC50 values for BuChE were higher (53.5–228.4 µM). 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 µM). 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.

Highlights

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia, with heavy social and economic costs and problems, which gradually worsen over a number of years [1,2]
When compared to analogous reaction performed under refluxing for 6 h, this MW-mediated synthesis offers shorter reaction time and higher yields (72–92%) [26]
The majority of these benzamides have been reported in our previous studies [15,17,26]; for details, see Section 2.1.2

Summary

Introduction

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most common cause of dementia, with heavy social and economic costs and problems, which gradually worsen over a number of years [1,2]. Fifty million people worldwide are living with dementia and the World Alzheimer report. 2018 estimates an incensement to more than 152 million cases by 2050 [3]. The brain contains two major forms of cholinesterases: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Both enzymes may have roles in the aetiology and progression of AD beyond regulation of synaptic ACh levels.

Methods

Results

Conclusion