Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the sixth leading cause of death worldwide, with cases continuing to rise at an alarming rate and imposing major social, economic, and healthcare burdens. Despite over a century of research, effective disease-modifying therapies remain elusive. Several pathogenic mechanisms—including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, acetylcholine deficiency, and oxidative stress—have been explored to elucidate AD progression. Among these, targeting the Aβ cascade has emerged as a particularly promising therapeutic strategy, especially in the early stages of the disease. Consequently, the development of small molecules capable of modulating amyloid aggregation represents a critical avenue for advancing novel AD treatments.
In this work, a novel library of N-benzylphenoselenazine (PSZ) derivatives (8a–j) was designed, synthesized, and systematically evaluated for their ability to inhibit Aβ40 aggregation, a central hallmark of AD pathology. Structure–activity relationship (SAR) studies using thioflavin T fluorescence assays demonstrated significant inhibition across the series, ranging from 26.0% to 86.4%. Compounds 8i and 8j exhibited particularly strong effects, reducing aggregation by ~75% and 86% at 25 μM, respectively—comparable to standard reference inhibitors resveratrol (~85%) and methylene blue (~96%). Transmission electron microscopy (TEM) confirmed their ability to disrupt Aβ40 fibril formation, while computational docking studies indicated favorable interactions with the hydrophobic KLVFFA motif of the Aβ40 dimer, stabilizing its structure and impeding further aggregation.
These findings establish N-benzylphenoselenazines as promising lead candidates for therapeutic development aimed at the amyloid cascade. By combining synthetic design, biological evaluation, and computational modeling, this study underscores the potential of selenium-based scaffolds as innovative agents for addressing the unmet therapeutic challenges of Alzheimer’s disease.
