Inhibition of Amyloid Fibrillization of Amyloid Β Peptide by 4,7-Disubstituted Coumarin Derivatives

Abstract

Coumarins are well-known for their unique chemical structure and a wide range of biological effects. Various substituted coumarin-based compounds have emerged as promising candidates for the development of novel therapeutic agents against numerous diseases. This study focuses on the synthesis of new 4,7-disubstituted coumarin derivatives and investigates their ability to inhibit the aggregation of the Aβ40 peptide, their cytotoxic effect on SH-SY5Y cells, their antioxidant properties, and their ability to penetrate the blood-brain barrier (BBB). The results reveal that the trihydroxy derivatives 5a-c are the most effective inhibitors of Aβ aggregation, promoting the formation of non-toxic, amorphous aggregates instead. Importantly, no significant decrease in the viability of SH-SY5Y neuroblastoma cells was observed after treatment with the studied coumarins. Among them, coumarin 5a demonstrated the strongest antioxidant activity, while compound 5b also exhibited good antioxidant properties, along with the best inhibition of Aβ aggregation (IC50 = 13.5 μM), and adequate permeability across the blood-brain barrier. These findings suggest that compound 5b is a promising candidate for further investigation in Alzheimer’s disease pharmacotherapy.

Note:
Funding declaration: We gratefully acknowledge the generous support provided by the Slovak Grant Agency VEGA (grant 1/0268/24; grant 1/0037/22; grant 02/0176/21); KEGA Project no. 007UPJŠ-4/2024; Slovak Research and Development Agency under the Contract no. APVV-18-0284 and APVV22-0598 and the ERDF ITMS2014+: 313011T553 “DIAGNAD”.

Conflict of Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors declared no conflict of interest.

Keywords: Coumarin derivatives, Alzheimer´s disease, Antioxidant activity, Aβ peptide, amyloid aggregation, cell viability assay