Key ADMET Parameters from admetSAR.

Alzheimer’s disease (AD) is a neurodegenerative disorder categorized by the progressive loss of cognitive function, with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as key therapeutic targets. In this study, we report the isolation, characterization, and evaluation of the cholinesterase inhibitory potential of phytochemicals from Fernandoa adenophylla (Wall. ex G. Don) Steenis, a plant known for its medicinal properties. Using in-vitro enzyme inhibition assays, we identified five bioactive compounds, including lapachol (1), α-lapachone (2), peshawaraquinone (3), dehydro-α-lapachone (4), and an indanone derivative (5), which demonstrated significant inhibition of AChE and BuChE. The compounds exhibited varied inhibitory potency, with peshawaraquinone (3) showing the most promising AChE (IC50 = 0.90 ± 0.04 µM) and BuChE (IC50 = 8.39 ± 0.14 µM) inhibition, followed by dehydro-α-lapachone (4), which exhibited an AChE IC50 value of 2.64 ± 0.08 µM. Further, the selectivity index (SI) for AChE over BuChE was highest for dehydro-α-lapachone (SI = 21.1), suggesting its potential as a selective inhibitor. Molecular docking studies provided insights into the binding interactions between these compounds and the enzyme active sites, highlighting key interactions that may contribute to their inhibitory activity. These findings suggest that phytochemicals from F. adenophylla possess significant cholinesterase inhibition potential and may serve as leads for the development of novel therapeutic agents for Alzheimer’s disease.