Novel Phenoselenazines as Amyloid-β Aggregation Inhibitors.

Area of Science:

• Medicinal Chemistry
• Neuroscience
• Biochemistry

Background:

• Amyloid-beta (Aβ42) aggregation is a central pathological hallmark of Alzheimer's disease.
• Developing effective inhibitors of Aβ42 aggregation is crucial for therapeutic intervention.

Purpose of the Study:

• To design, synthesize, and evaluate novel N-benzylphenoselenazine derivatives as inhibitors of Aβ42 aggregation.
• To assess the disaggregation and antioxidant properties of these compounds.
• To investigate their potential in reducing Aβ42-mediated cytotoxicity.

Main Methods:

• Synthesis of N-benzylphenoselenazine derivatives.
• Thioflavin T-based fluorescence assay to monitor Aβ42 aggregation kinetics.
• Cell-based assays to evaluate cytotoxicity.
• Computational modeling to understand the mechanism of interaction.

Main Results:

• Compounds 8i and 8j demonstrated significant inhibition of Aβ42 aggregation (∼91%), comparable to resveratrol and methylene blue.
• Both compounds exhibited Aβ42 disaggregation (up to 76%) and antioxidant activity (up to 80.5%).
• Compounds 8i and 8j reduced Aβ42-mediated cytotoxicity in cell culture.
• Computational studies indicated interaction within the Aβ42 pentamer channel, stabilizing the assembly.

Conclusions:

• N-benzylphenoselenazine derivatives are effective inhibitors of Aβ42 aggregation.
• These compounds display multifaceted therapeutic potential, including disaggregation and antioxidant effects.
• N-benzylphenoselenazines represent promising candidates for targeting the amyloid cascade in Alzheimer's disease therapy.