New Benzodihydrofuran Derivatives Alter the Amyloid β Peptide Aggregation: Strategies To Develop New Anti-Alzheimer Drugs.

Abstract

Alzheimer's disease is a neurodegenerative disorder that is the leading cause of dementia in elderly patients. Amyloid-β peptide (1-42 oligomers) has been identified as a neurotoxic factor, triggering many neuropathologic events. In this study, 15 chalcones were synthesized employing the Claisen-Schmidt condensation reaction, starting from a compound derived from fomannoxine, a natural benzodihydrofuran whose neuroprotective activity has been proven and reported, and methyl aromatic ketones with diverse patterns of halogenated substitution. As a result, chalcones were obtained, with good to excellent reaction yields from 50 to 98%. Cytotoxicity of the compounds was assessed, and their cytoprotective effect against the toxicity associated with Aβ was evaluated on PC-12 cells. Out of the 15 chalcones obtained, only the 4-bromo substituted was cytotoxic at most tested concentrations. Three synthesized chalcones showed a cytoprotective effect against Aβ toxicity (over 37%). The 2,4,5-trifluoro substituted chalcone was the most promising series since it showed a cytoprotective impact with more than 60 ± 5% of recovery of cellular viability; however, 3-fluoro substituted compound also exhibited important values of recovery (50 ± 6%). The fluorine substitution pattern was shown to be more effective for cytoprotective activity. Specifically, substitution with fluorine in the 3,5-positions turned out to be particularly effective for cytoprotection. Furthermore, fluorinated compounds inhibited the aggregation rate of Aβ, suggesting a dual effect that can be the starting point of new molecules with therapeutic potential.