Chalcones as Multi-target Ligands for Alzheimer's Disease: A Review of Synthetic Strategies and Therapeutic Promise.

Abstract

Introduction: Alzheimer's disease remains a multifactorial neurodegenerative disorder with limited therapeutic options. Chalcones, flavonoid-derived molecules with high structural flexibility and diverse biological activities, have emerged as promising candidates due to their ability to inhibit Aβ aggregation and cholinesterase activity. Recent research highlights their relevance as multi-target agents suitable for early-stage drug discovery.

Methods: This review compiled and analyzed studies published between 2022 and 2025 on chalcones and their derivatives with anti-Alzheimer's potential. Data were extracted regarding biosynthetic origins, synthetic strategies, physicochemical properties, and biological activities, including inhibitory potencies against AChE, MAO-B, and Aβ aggregation.

Results: Numerous chalcone-based compounds exhibited significant activity against key Alzheimer's disease targets, such as Aβ1-42 aggregation (up to 78.2% inhibition) and enzymatic inhibition (e.g., AChE IC50 = 11.6 nM; MAO-B IC50 = 92 nM). Their structural versatility enabled the identification of potent derivatives with multi-target effects, addressing oxidative stress, amyloid pathology, and cholinergic dysfunction.

Discussion: Chalcones represent a privileged scaffold suitable for medicinal chemistry optimization, offering ease of synthesis and adaptable chemical space for structure-activity relationship exploration. Their multi-target nature aligns with the complexity of Alzheimer's disease. However, challenges remain, including selectivity, pharmacokinetics, and translation from preclinical models to therapeutic relevance.

Conclusion: Chalcones and their derivatives show strong preclinical promise as multi-target agents for Alzheimer's disease. Continued structural optimization and biological evaluation may advance these compounds toward disease-modifying therapies, supporting their potential role in future drug discovery efforts.