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 them (5, 8, 11, 17, 19, 21-23, 26-28) exhibited significant effects with the IC50 values ranged 0.88 to 1.28 mu M. 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 pi-pi stacking with the indole and phenol side chains of Trp86 and Tyr337, besides the hydrogen bonding with the hydration site and pi-pi 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.

Automated summary

A new series of 3-O-substituted xanthone derivatives were synthesized and evaluated for their anti-cholinergic activities against AChE and BChE. The results showed that eleven of these derivatives exhibited significant AChE inhibitory activity with IC50 values ranging from 0.88 to 1.28 μM. Molecular docking study revealed that compound 23 interacts with the active site of AChE through extensive pi-pi stacking and hydrogen bonding.