Abstract
Chalcone is a versatile scaffold that has gained attention for its potential in developing
treatments for Alzheimer’s disease (AD). This review highlights recent progress in
the design and evaluation of chalcone hybrids and derivatives with anti-Alzheimer
activity, particularly against key enzymes such as acetylcholinesterase (AChE), butyrylcholinesterase
(BChE), and monoamine oxidases (MAO-A and MAO-B). Many of these compounds show promising
inhibition, suggesting their potential to improve cholinergic transmission and reduce
neurodegeneration. Structure–activity relationship (SAR) studies reveal that substitution
patterns on aromatic rings strongly influence activity. Oxindole-based chalcone analogues
(5) were good AChE inhibitors, while chalcone–rivastigmine hybrids (11) were excellent
BChE inhibitors. For MAO-B, 4-aminochalcone–rivastigmine hybrids (10) and morpholine-based
chalcone hybrids (20) were potent inhibitors. Molecular docking studies further explain
how these molecules interact with target enzymes, supporting their biological relevance.
The combination of pharmacophores with the chalcone core has also improved selectivity
and potency. Overall, the findings summarized in this review suggest that chalcone-based
compounds are promising candidates for further development as anti-Alzheimer agents.
With their multitarget potential and ease of structural modification, chalcones represent
a valuable pharmacophore for addressing the complex pathology of AD. Future work focusing
on rational design and computational tools may enable the discovery of effective therapies.
Keywords
Alzheimer’s disease - Acetylcholinesterase - Hybrids - Chalcone - Docking
