Amyloid-beta aggregation and advanced glycation end-products inhibitory activities of Pandanus amaryllifolius Roxb. alkaloids: insights from in vitro and computational investigations

Abstract

Alzheimer's disease (AD) is characterized by cognitive decline and behavioral changes, with the formation of amyloid-beta (Aβ) plaques as one of the underlying mechanisms responsible for its progression. Advanced glycation end-products (AGEs) have also been linked to AD pathology, contributing to oxidative stress and amyloid plaque formation. Pandanus amaryllifolius has shown potential in inhibiting Aβ aggregation and AGE formation, suggesting a multifaceted approach for managing AD. In this study, alkaloids isolated from the crude base extract of P. amaryllifolius leaves were explored for their in vitro inhibitory effects on AGEs formation and Aβ aggregation. Results showed that pandamarilactonines A (3) (74% at 100 μg/mL and 50% at 50 μg/mL) and B (8) (56% at 100 μg/mL and 34% at 50 μg/mL) exhibited highest inhibitory activities on AGEs formation using the BSA-dextrose model. Pandamarilactonine A (3) (74%) also exhibited Aβ aggregation inhibition, along with pandanusine B (4) (66%) and pandamarilactonine B (8) (63%), using the Thioflavin T assay. Molecular docking studies further supported these findings, revealing strong binding affinities between the alkaloids and Aβ oligomeric structures. Pandamarilactonine A (3) and pandamarilactonine B (8) showed the best binding affinity to the Aβ dodecameric structure (BE = − 7.5 to − 7.7 kcal/mol), thus corroborating with the in vitro results. Hence, these findings suggest that the Pandanus alkaloids could serve as promising candidates for further development as therapeutic agents against AD. However, in vivo studies are necessary to validate these findings, and further exploration of the structure–activity relationships could aid in the rational design of drug candidates utilizing the Pandanus alkaloids.