Synthesis and biological evaluation of 1, 3-dihydroxyxanthone mannich base derivatives as anticholinesterase agents

Abstract

Background: Alzheimer's disease (AD), a progressive and degenerative disorder, has become one of the severe problems among the aged population all over the world. To use cholinesterase inhibitor drugs has become the most predominant treatment strategy for AD.

Results: A series of novel 1, 3-dihydroxyxanthone Mannich bases derivatives (1a ~ 4e) were synthesized, structure elucidated and evaluated for anti-cholinesterase activity. The result showed that most of the target compounds exhibited moderate to good inhibitory activities with the IC50 values at micromole level concentration against both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The preliminary structure-activity indicated that: (i) The alkoxy or alkenoxy substituents in the position 3 of xanthone have a positive influence on the inhibition potency; (ii) types of dialkylamine methyl in position 2 of xanthone affected cholinesterase activities and AChE/BuChE selectivity. Among them, 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one showed potent inhibitory activity against AChE with the IC50 value of 2.61 ± 0.13 μM and the best inhibitory activity against BuChE with the IC50 value of 0.51 ± 0.01 μM. The results of a mixed-type manner in enzyme kinetic experiment and molecular docking study for 2-((diethylamino)methyl)-1-hydroxy-3-(3-methylbut-2-enyloxy)-9H-xanthen-9-one demonstrated that the Mannich base derivatives were likely to bind to the active site (AS) and the peripheral anionic site (PAS) of cholinesterases.

Conclusions: This study suggested that 1, 3-dihydroxyxanthone Mannich base derivatives were potential dual inhibitors of both AChE and BuChE, which may be considered as a kind of novel drug candidates for treatment of AD.

Scheme 1

Synthetic route of 1, 3-dihydroxyxanthone mannich base derivatives.

Figure 1

Main connectivities found in the HMBC of Compound 2c.

Figure 2

Effects of substitution in position 2 of xanthone against AChE and BuChE, respectively. 1, 2, 3, 4 represent hydroxyl, methoxyl, allyloxy, prenylated oxyl substituted in the position 3 of xanthone, respectively. a, b, c, d, e represent diethylamine methyl, dimethylamine methyl, pyrrolidinyl methyl, piperidinyl methyl, morpholino methyl substituted in the position 2 of xanthone, respectively.

Figure 3

Effects of substitution in position 3 of xanthone against AChE and BuChE, respectively. 1, 2, 3, 4 represent hydroxyl, methoxyl, allyloxy, prenylated oxyl substituted in the position 3 of xanthone, respectively. a, b, c, d, e represent diethylamine methyl, dimethylamine methyl, pyrrolidinyl methyl, piperidinyl methyl, morpholino methyl substituted in the position 2 of xanthone, respectively.

Figure 4

Lineweaver-Burk plots of AChE and BuChE inhibitory activity in the presence of compound 4b.

Figure 5

The binding mode research of compound 4b on AChE by docking simulations. (A) Binding interactions with selected residues of the active site for compound 4b. (B) The MOLCAD surfaces displayed with cavity depth potential of the binding pocket. (C) The MOLCAD surfaces of the binding pocket displayed with lipophilic potential.

Figure 6

The binding mode research of compound 4b on BuChE by docking simulations. (A) The binding interactions with selected residues of the active site for compound 4b. (B) The MOLCAD surfaces displayed with cavity depth potential of the binding pocket. (C) The MOLCAD hydrogen bonding surfaces of the binding pocket.