Ferulic acid amide derivatives with varying inhibition of amyloid-β oligomerization and fibrillization

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized, in part, by the misfolding, oligomerization and fibrillization of amyloid-beta (A beta). Evidence suggests that the mechanisms underpinning A beta oligomerization and subsequent fibrillization are distinct, and may therefore require equally distinct therapeutic approaches. Prior studies have suggested that amide derivatives of ferulic acid, a natural polyphenol, may combat multiple AD pathologies, though its impact on A beta aggregation is controversial. We designed and synthesized a systematic library of amide derivatives of ferulic acid and evaluated their anti-oligomeric and anti-fibrillary capacities independently. Azetidine tethered, triphenyl derivatives were the most potent anti-oligomeric agents (compound 2i: IC50 = 1.8 mu M +/- 0.73 mu M); notably these were only modest anti-fibrillary agents (20.57% inhibition of fibrillization), and exemplify the poor correlation between anti-oligomeric/fibrillary activities. These data were subsequently codified in an in silico QSAR model, which yielded a strong predictive model of anti-A beta oligomeric activity (kappa = 0.919 for test set; kappa = 0.737 for validation set).

Automated summary

Alzheimer's disease is a progressive neurodegenerative disorder characterized by misfolding and fibrillization of amyloid-beta. Studies have shown that amide derivatives of ferulic acid may combat AD pathologies, with one compound exhibiting potent anti-oligomeric but modest anti-fibrillary effects, highlighting the poor correlation between these activities. An in silico QSAR model was developed to predict anti-A beta oligomeric activity with high accuracy.