New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors

A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of t...

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Bibliographic Details
Published in:Journal of enzyme inhibition and medicinal chemistry 2021-01, Vol.36 (1), p.627-639
Main Authors: Loh, Zi Han, Kwong, Huey Chong, Lam, Kok Wai, Teh, Soek Sin, Ee, Gwendoline Cheng Lian, Quah, Ching Kheng, Ho, Anthony Siong Hock, Mah, Siau Hui
Format: Article
Language:English
Subjects:
Acetylcholinesterase - metabolism
Alzheimer's disease
Animals
Butyrylcholinesterase - metabolism
Cholinesterase Inhibitors - chemical synthesis
Cholinesterase Inhibitors - chemistry
Cholinesterase Inhibitors - pharmacology
Crystallography, X-Ray
Dose-Response Relationship, Drug
Electrophorus
enzyme kinetic study
Horses
Models, Molecular
molecular docking
Molecular Structure
Research Paper
Structure-Activity Relationship
structure-activity relationship study
synthesis
Xanthones - chemical synthesis
Xanthones - chemistry
Xanthones - pharmacology
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Summary:A new series of 3-O-substituted xanthone derivatives were synthesised and evaluated for their anti-cholinergic activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results indicated that the xanthone derivatives possessed good AChE inhibitory activity with eleven of them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC 50 values ranged 0.88 to 1.28 µM. The AChE enzyme kinetic study of 3-(4-phenylbutoxy)-9H-xanthen-9-one (23) and ethyl 2-((9-oxo-9H-xanthen-3-yl)oxy)acetate (28) showed a mixed inhibition mechanism. Molecular docking study showed that 23 binds to the active site of AChE and interacts via extensive π-π stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and π-π interaction with the phenol side chain of Y72. This study revealed that 3-O-alkoxyl substituted xanthone derivatives are potential lead structures, especially 23 and 28 which can be further developed into potent AChE inhibitors.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2021.1882452