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 microM. 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.
        
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Loh ZH, Kwong HC, Lam KW, Teh SS, Ee GCL, Quah CK, Ho ASH, Mah SH (2021) New 3-O-substituted xanthone derivatives as promising acetylcholinesterase inhibitors J Enzyme Inhib Med Chem36: 627-639
Loh ZH, Kwong HC, Lam KW, Teh SS, Ee GCL, Quah CK, Ho ASH, Mah SH (2021) J Enzyme Inhib Med Chem36: 627-639