Format

Send to

Choose Destination
Biomolecules. 2019 Nov 5;9(11). pii: E698. doi: 10.3390/biom9110698.

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

Author information

1
Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University, Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic.
2
Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, Studentská 573, 532 10 Pardubice, Czech Republic.

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.

KEYWORDS:

acetylcholinesterase; benzamides; butyrylcholinesterase; enzyme inhibition; esters; in vitro inhibition; phosphorus derivatives; salicylanilides

PMID:
31694272
DOI:
10.3390/biom9110698
Free full text

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI)
Loading ...
Support Center