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

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 Aβ_1-42-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) Aβ_1-42 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 Aβ_1-42 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.

acetylcholinesterase; amyloid beta aggregation; molecular docking; multi-target drug; neuroprotection; structure–activity relationship.