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Open AccessArticle

Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease

1
Faculty of Pharmaceutical Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
2
Faculty of Pharmaceutical Sciences, Ubon Ratchathani University, Ubon Ratchathani 34190, Thailand
3
Faculty of Sciences, Khon Kaen University, Khon Kaen 40002, Thailand
4
Center for Research and Development of Herbal Health Products, Khon Kaen University, Khon Kaen 40002, Thailand
5
Department of Chemical Technology, Faculty of science, Chulalongkorn University, Bangkok 10330, Thailand
6
Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming 650223, China
*
Author to whom correspondence should be addressed.
Biomedicines 2020, 8(5), 107; https://doi.org/10.3390/biomedicines8050107
Received: 4 April 2020 / Revised: 29 April 2020 / Accepted: 30 April 2020 / Published: 2 May 2020
Coumarins, naturally occurring phytochemicals, display a wide spectrum of biological activities by acting on multiple targets. Herein, nine coumarins from the root of Toddalia asiatica were evaluated for activities related to pathogenesis of Alzheimer’s disease (AD). They were examined for acetylcholinesterase (AChE) and AChE- or self-induced amyloid beta (Aβ) aggregation inhibitory activities, as well as neuroprotection against H2O2- and Aβ1–42-induced human neuroblastoma SH-SY5Y cell damage. Moreover, in order to understand the mechanism, the binding interactions between coumarins and their targets: (i) AChE and (ii) Aβ1–42 peptide were investigated in silico. All coumarins exhibited mild to moderate AChE and self-induced Aβ aggregation inhibitory actions. In addition, the coumarins substituted with the long alkyl chain at position 6 or 8 illustrated ability to inhibit AChE-induced Aβ aggregation, resulting from their dual binding site at catalytic anionic site and peripheral active site in AChE. Moreover, the most potent multifunctional coumarin, phellopterin, could attenuate neuronal cell damage induced by H2O2 and Aβ1–42 toxicity. Conclusively, seven out of nine coumarins were identified as multifunctional agents inhibiting the pathogenesis of AD. The structure–activity relationship information obtained might be applied for further optimization of coumarins into a useful drug which may combat AD. View Full-Text
Keywords: acetylcholinesterase; amyloid beta aggregation; neuroprotection; molecular docking; multi-target drug; structure–activity relationship acetylcholinesterase; amyloid beta aggregation; neuroprotection; molecular docking; multi-target drug; structure–activity relationship
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Takomthong, P.; Waiwut, P.; Yenjai, C.; Sripanidkulchai, B.; Reubroycharoen, P.; Lai, R.; Kamau, P.; Boonyarat, C. Structure–Activity Analysis and Molecular Docking Studies of Coumarins from Toddalia asiatica as Multifunctional Agents for Alzheimer’s Disease. Biomedicines 2020, 8, 107.

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