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

Abstract

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.

Antidementia Effects of Alternanthera philoxeroides in Ovariectomized Mice Supported by NMR-Based Metabolomic Analysis

“…The ThT assay for evaluation of the Aβ1-42 self-aggregation process was performed according to the previously described procedure [ 40 ]. Briefly, Aβ1-42 was solubilized with 50 mM phosphate buffer (pH 7.4) to give a 250 µM stock solution.…”

Nordentatin Inhibits Neuroblastoma Cell Proliferation and Migration through Regulation of GSK-3 Pathway

“…Several studies have introduced coumarins as potential multi-target agents with a wide spectrum of pharmacological effects [21,22]. Coumarins, naturally occurring phyto-chemicals, have been reported as promising anticancer compounds against several types of cancer via different mechanisms [23][24][25][26].…”

Multi-Target Actions of Acridones from Atalantia monophylla towards Alzheimer’s Pathogenesis and Their Pharmacokinetic Properties

“…To perform the molecular docking studies, an AChE template was prepared from an X-ray crystal structure (PDB code: 2CEK) and validated by six AChE inhibitors 2CEK, 1H22, 1ZGB, 2CMF, 1ODC, and 1UT6 [ 64 ]. All water and other solvent molecules in the templates of AChE were extracted and hydrogens, Gasteiger charges, and merged non-polar hydrogen atoms were added.…”