Novel Phenoselenazines as Amyloid-β Aggregation Inhibitors

A novel library of <i>N</i>-benzylphenoselenazine derivatives <b>8a</b>-<b>j</b> were designed, synthesized, and evaluated as inhibitors of amyloid-beta (Aβ42) aggregation. In the thioflavin T-based fluorescence aggregation kinetics assay, compounds <b>8i</b> and <b>8j</b> exhibited excellent inhibition of Aβ42 aggregation (∼91% inhibition at 25 μM), and the activity was comparable to that of reference agents resveratrol (∼88%) and methylene blue (∼95% inhibition). Both compounds also demonstrated Aβ42 disaggregation properties (58% and 76% respectively at 25 μM) and antioxidant activity (80.5% and 59% respectively at 25 μM). In the cell culture studies, both <b>8i</b> and <b>8j</b> were able to reduce Aβ42-mediated cytotoxicity. Computational studies suggest that these compounds interact in a narrow channel formed by the N- and C-termini in the Aβ42 pentamer model to stabilize the assembly and prevent further aggregation. These results demonstrate the viability of the <i>N</i>-benzylphenoselenazines as promising candidates to target the amyloid cascade in Alzheimer's disease.