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

Abstract

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 mM. 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 p-p stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and p-p 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.

Synthesis of 1-Hydroxy-3-O-Substituted Xanthone Derivatives and their Structure-activity Relationship on Acetylcholinesterase Inhibitory Effect

“…The xanthones bearing phenylpropyl (2o) and phenylbutyoxyl (2p) groups showed a signi cant increase in AChE inhibition levels, which are about 80%-85% stronger than 1. Similar ndings were observed in our previous study, whereby the substitution of the hydroxyl group at C-3 with a phenylpropxyl or phenylbutoxyl group resulted in 48%-63% stronger anti-AChE effects compared to its parent, 3-hydroxyxanthone 33 . This observation is in agreement with several previous reports indicating that arene groups in xanthones allow stronger binding a nity to AChE through hydrophobic π-π interactions with Trp84 in the choline-binding pocket [46][47][48][49] .…”

“…The IC 50 value obtained for 1 was 157.47 µM, which is close to that of previously published data by Thongchai et al (2014) with 150.61 µM) 36 . The inhibition activity of 1 is signi cantly weaker than 3-hydroxyxanthone, which has an IC 50 value of 2.4 µM against AChE 33 . This nding shows that the hydroxyl group at position C-1 of xanthone failed to contribute favourable effects to anti-AChE activities.…”

“…Compound 2g was then prepared and minimised before the docking procedure. The DS Flexible Docking module was adopted for the receptor-ligand docking 33 . The ligand was docked to the active site of each receptor conformation using LibDock.…”

“…The concentrations of the 2g and 2j used were 7.5, 10, 12.5 and 15 µM. Then, Lineweaver-Burk plots were obtained by plotting reciprocal velocity versus substrate 33 .…”

Statistical model for IC₅₀ determination of acetylcholinesterase enzyme for Alzheimer’s disease

“…Overall, the lowest mean of IC50 exhibited by compound 3 (31.84 μg/mL) indicated its most substantial inhibition among the compounds, followed by compounds 6 (50.82 μg/mL) and 10 (57.15 μg/mL). However, the mean of IC50 obtained for these compounds showed that their inhibition effect was moderate if compared to the common standard drug tacrine, used in the Ellman's assay [42].…”