Dual Inhibition of AChE and BACE-1 by Novel Multi-Target-Directed Ligands: Design, Synthesis, and Biological Evaluation for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is characterized by cognitive decline, amyloid-β accumulation, tau hyperphosphorylation, and cholinergic deficit, while current therapies offer only symptomatic relief. This study aimed to design and synthesize novel multi-target-directed ligands (MTDLs) capable of dual inhibition of acetylcholinesterase (AChE) and β-secretase (BACE-1). Pharmacophore hybrids derived from donepezil and coumarin scaffolds were designed through molecular docking and ADMET screening, synthesized, and characterized by IR, NMR, and MS. In vitro assays revealed several compounds with potent dual inhibition in the nanomolar range, confirmed dual binding modes, and demonstrated strong antioxidant activity and >60 % neuroprotection in oxidative-stress models. These MTDLs exhibit promising multitarget and neuroprotective potential as candidates for disease-modifying Alzheimer’s therapy.