Medicinal Chemistry Approaches in the Discovery of Therapeutics for Alzheimer’s Disease: Progress and Perspectives

Abstract

Amyloid-β buildup, tau hyperphosphorylation, cholinergic dysfunction, oxidative stress, and neuroinflammation are all hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative illness. Recent anti-amyloid antibodies like aducanumab and lecanemab offer limited disease-modifying benefits with safety concerns, while currently approved FDA medications, such as memantine and cholinesterase inhibitors, only relieve symptoms. Through structure-based design, SAR optimization, and the creation of innovative scaffolds, medicinal chemistry is essential to the advancement of AD therapies. Designing cholinesterase inhibitors, β-/γ-secretase inhibitors, tau aggregation blockers, antioxidants, and metal chelators are important tactics. In order to address the multifactorial nature of AD, multi-target directed ligands, or MTDLs, are becoming more and more popular. Strong synthetic analogs with enhanced brain penetration are inspired by natural leads such as resveratrol, curcumin, and huperzine A. AI, pharmacophore modeling, QSAR, and docking are computational tools that speed up hit identification and optimization. Promising directions for future AD treatments are provided by developments in prodrugs, lipophilic modifications, and nanocarriers, which further improve BBB delivery.