In addition to amyloid cascade hypothesis, ferroptosis - a recently identified cell death pathway associated with the accumulation of lipid hydroperoxides - was hypothesized as one of the main forms of cell death in Alzheimer's disease. Herein, a series of hydroxylated chalcones were designed and synthesized as dual-functional inhibitors to inhibit amyloid-β peptide (Aβ) aggregation as well as ferroptosis simultaneously. Thioflavin-T assay indicated trihydroxy chalcones inhibited Aβ aggregation better. In human neuroblastoma SH-SY5Y cells, cytoprotective chalcones 14a-c with three hydroxyl substituents exhibited a significant neuroprotection against Aβ1-42 aggregation induced toxicity. In addition, chalcones 14a-c were found to be good inhibitors of ferroptosis induced by either pharmacological inhibition of the hydroperoxide-detoxifying enzyme Gpx4 using (1S, 3R)-RSL4 or cystine/glutamate antiporter system Xc- inhibition by erastin through lipid peroxidation inhibition mechanism. Trihydroxy chalcone 14a was also able to completely subvert lipid peroxidation induced by Aβ1-42 aggregation in SH-SY5Y cells indicating that they can reduce the neurotoxicity involved with oxidative stress. Compound 14a-c showed good ADMET properties and blood-brain barrier penetration in silico simulation software. From these data, a picture emerges wherein trihydroxy chalcones are potential candidates for the treatment of Alzheimer's disease by simultaneously inhibition of Aβ1-42 aggregation and ferroptosis.
Keywords: Alzheimer's disease; Amyloid-β aggregation inhibition; Chalcone derivatives; Ferroptosis inhibition.
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