Issue 126, 2015

Synthesis and evaluation of 6-substituted 3-arylcoumarin derivatives as multifunctional acetylcholinesterase/monoamine oxidase B dual inhibitors for the treatment of Alzheimer’s disease

Abstract

Considering the complex etiology of Alzheimer’s disease (AD), multifunctional agents may exhibit important properties against this disease. A series of 6-substituted 3-arylcoumarins (5a–t) were designed, synthesized and evaluated as cholinesterase (ChE) and monoamino oxidase (MAO) inhibitors. Among them, compounds 5o [IC50, 195 nM for human acetylcholinesterase (hAChE), selectivity index, SI (human butyrylcholinesterase, hBuChE/hAChE) = 145; IC50, 63.5 nM for human monoamine oxidase-B (hMAO-B), SI (human monoamine oxidase-A, hMAO-A/hMAO-B) = 25] and 5p [IC50, 185 nM for hAChE, SI (hBuChE/hAChE) = 182; IC50, 196 nM for hMAO-B, SI (hMAO-A/hMAO-B) > 510] were found to selectively inhibit both hAChE and hMAO-B with IC50 values in the nanomolar range. The abilities of 5o and 5p to bind to hAChE and hMAO-B were confirmed by molecular docking and kinetic studies. Moreover, 5o and 5p were found to exhibit significant inhibition of self-induced Aβ42 aggregation (61% and 52%, at 20 μM), have antioxidant properties (0.81 and 1.17 trolox equivalent by ABTS assay), provide neuroprotection against Aβ42-induced cytotoxicity and blood–brain barrier (BBB) penetration capacity (PAMPA-BBB+), and are thus potential anti-Alzheimer agents with balanced activities. Overall, the study provided meaningful information for further development of multifunctional drugs for AD therapy.

Graphical abstract: Synthesis and evaluation of 6-substituted 3-arylcoumarin derivatives as multifunctional acetylcholinesterase/monoamine oxidase B dual inhibitors for the treatment of Alzheimer’s disease

Supplementary files

Article information

Article type
Paper
Submitted
24 oct. 2015
Accepted
20 nov. 2015
First published
10 déc. 2015

RSC Adv., 2015,5, 104122-104137

Synthesis and evaluation of 6-substituted 3-arylcoumarin derivatives as multifunctional acetylcholinesterase/monoamine oxidase B dual inhibitors for the treatment of Alzheimer’s disease

Z. Wang, X. Li, G. Xue, W. Xu, X. Wang and L. Kong, RSC Adv., 2015, 5, 104122 DOI: 10.1039/C5RA22296F

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