Design, Synthesis, and Evaluation of Novel Phenoselenazine Derivatives as Potent Modulators of Aβ42 Aggregation

A novel class of fused tricyclic phenoselenazine derivatives possessing a redox-active selenium atom were designed, synthesized, and evaluated as Aβ42 aggregation inhibitors with antioxidant activity. They exhibit remarkable inhibition of Aβ42 aggregation as confirmed by fluorescence aggregation kinetics study, electron microscopy, and cell-based studies in mouse hippocampal HT22 neuronal and BV2 microglial cells. Compounds 5i and 9g exhibited potent inhibition of Aβ42 aggregation with IC50 values of 350 and 317 nM, respectively, with compound 9g exhibiting exceptional ability to destabilize preformed Aβ42 fibrils (IC50 = 210 nM), surpassing those of the reference compounds resveratrol and methylene blue. Both 5i and 9g showed efficient blood-brain barrier permeability and provided significant neuroprotection toward Aβ42-induced cytotoxicity and demonstrated strong antioxidant properties by conferring protection toward hydrogen peroxide-induced cytotoxicity in mouse hippocampal HT22 cells. Collectively, our results demonstrate that these novel phenoselenazines represent a promising class of therapeutics to treat Alzheimer's disease.