Novel Amyloid-β Aggregation Inhibitors Based on Phenylalanine Structure.

INTRODUCTION/OBJECTIVE: Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) aggregation, making its inhibition a promising therapeutic strategy. This study evaluated the effects of two phenylalanine derivatives on Aβ aggregation and associated neurotoxicity. METHODS: Interactions between Aβ monomer and two compounds (12a and 5g) were explored by molecular docking. The inhibitory effects of the compounds on Aβ aggregation were evaluated using a thioflavin-T (ThT) assay, transmission electron microscopy (TEM), and dot blot. The neuroprotective ability of the two compounds was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide (MTT) assay. RESULTS: Docking analysis revealed that compounds 12a and 5g can bind to monomeric Aβ and identified the amino acids responsible for the interactions. The two compounds significantly reduced ThT fluorescence during the 48-hour incubation at all concentrations in ThT kinetics assays. The inhibitory effects were further confirmed in TEM. Both compounds suppressed Aβ oligomerization (reductions to 42.72% and 35.90% of the untreated control group, respectively). Furthermore, compound 5g, with a new structure, showed remarkable protection (cell viability increased to 97.86% of the control) against Aβ oligomer-treated human neuroblastoma SH-SY5Y cells, while having no intrinsic effect on cell viability. DISCUSSION: Compounds 12a and 5g act as more specific Aβ oligomerization inhibitors than traditional polyphenols such as (-)-epigallocatechin-3-gallate (EGCG). The results may provide molecular insights for the rational design of potent Aβ aggregation inhibitors for AD therapy. CONCLUSION: This study demonstrates that phenylalanine derivatives hold great promise as novel AD therapeutic leads.