Novel Phenoselenazines as Amyloid-β Aggregation Inhibitors

  • ACS Med Chem Lett. 2025 Mar 17;16(4):567-574. doi: 10.1021/acsmedchemlett.4c00600.
Ahmed A Hefny  1  2 ,  Kartar Singh  1 ,  Rahul C Karuturi  1 ,  Arash Shakeri  1 ,  Michael A Beazely  1 ,  Praveen P N Rao  1
Affiliations
  • 1. School of Pharmacy, Health Sciences Campus, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G1, Canada.
  • 2. Medicinal Chemistry Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
PMID: 40236527 DOI: 10.1021/acsmedchemlett.4c00600
Abstract

A novel library of N-benzylphenoselenazine derivatives 8a-j were designed, synthesized, and evaluated as inhibitors of amyloid-beta (Aβ42) aggregation. In the thioflavin T-based fluorescence aggregation kinetics assay, compounds 8i and 8j 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 8i and 8j 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 N-benzylphenoselenazines as promising candidates to target the amyloid cascade in Alzheimer's disease.

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