Synthesis, In Silico, and In Vitro Evaluation of a Coumarin-Based Schiff Base as a Potential Anti-Alzheimer's Agent

AbstractThis study investigates the anti-Alzheimer’s potential of coumarin-based Schiff bases. Among the series of synthesized compounds, the phenyl hydrazine derivative of 3-Acetyl coumarin (PHC) was selected based on its high docking score. Given the limited treatment options for Alzheimer’s disease (AD), this research aims to explore novel therapeutic approaches using coumarin derivatives. In silico studies demonstrated strong binding interactions of PHC with acetylcholinesterase (AChE), with a binding affinity of -10.7 kcal/mol, supporting its role as a multi-target directed ligand. Pharmacokinetic evaluations using Swiss ADME software indicated favourable drug-like properties, including good gastrointestinal absorption, blood-brain barrier permeability, and compliance with Lipinski’s rule of five. In vitro assays showed that PHC effectively inhibits AChE, with an IC₅₀ value of 52.08 μg/mL. Notably, it interacts with both the catalytic active site and the peripheral anionic site of AChE, enhancing its potential as a multi-target ligand. Additionally, PHC exhibited moderate antioxidant activity, which may help mitigate oxidative stress, a key factor in AD pathology. These findings indicate that PHC holds significant anti-Alzheimer's potential through its multifunctional properties, highlighting its promise as a therapeutic candidate for AD.KeywordsAcetylcholinesterase (AChE) inhibition, Alzheimer’s disease, Coumarin, multi-target ligand, Schiff base.