Design, Synthesis, and Biological Evaluation of Multi-Target-Directed Ligands for Alzheimer's Disease: A Dual-Inhibitor Approach Targeting AChE and BACE-1

Abstract

Background: Alzheimer‘s disease (AD) involves cognitive decline, amyloid-β accumulation, tau hyperphosphorylation, and cholinergic loss. Current treatments provide only symptomatic relief. Objective: To design, synthesize, and evaluate novel multi-target-directed ligands (MTDLs) capable of dual inhibition of acetylcholinesterase (AChE) and β-secretase (BACE-1). Methods: Pharmacophore hybrids from donepezil and coumarin scaffolds were designed using molecular docking and ADMET screening, synthesized, and characterized by IR, NMR, and MS. In vitro assays evaluated AChE and BACE-1 inhibition, antioxidant potential, and neuroprotective effects. Results: Several compounds showed potent dual inhibition (low nanomolar IC₅₀ values) against both targets, validated dual binding modes, and significant antioxidant activity. Selected MTDLs demonstrated >60% neuroprotection in oxidative stress-induced cell models. Conclusion: The synthesized MTDLs exhibit strong multi-target activity and neuroprotective potential, representing promising leads for the development of disease-modifying therapies in AD.