Cholinesterase inhibitors assessment of aporphine alkaloids from Annona crassiflora and molecular docking studies

Abstract

Annona crassiflora Mart. is an endemic plant from Brazilian Cerrado (savanna) biome, commonly employed in traditional medicine to treat wounds, diarrhea, and scalp infections. The pulp of the fruits is edible and has a characteristic taste, being employed to prepare sweets like jam, cakes, and ice cream by the people who live in the region of the Cerrado, although the peels are discarded. In this way, the A. crassiflora fruit peels ethanol extract was prepared and subjected to liquid–liquid extraction, which yielded the alkaloidal fraction (CH2Cl2). Subjected to high-performance liquid chromatography separations, this fraction allowed the purification of the aporphine alkaloids stephalagine (1), liriodenine (2), and atherospermidine (3), that were structurally characterized by high-resolution mass spectrometry with electrospray ionization, and nuclear magnetic resonance spectroscopy analyses. Aporphine alkaloids are recognized for their acetylcholinesterase (AChE) inhibitory activity, an important target in Alzheimer's disease therapy. Thus, the ethanol extract, alkaloidal fraction, and compounds1,2,and3were evaluated for acetyl- and butyrylcholinesterase (BChE) inhibitory activities. Compound1(IC50 104.2 µmol L–1) exhibited better BChE inhibitory activity than the standard compound galanthamine (IC50 162.7 µmol L–1), while2had a comparable result(and IC50 167.3 µmol L–1). Furthermore, molecular docking was performed to predict the compound's binding mode to the human AChE at a molecular level. Semiempirical calculation results show that the enthalpy interaction energy (ΔHint) between AChE and BChE active sites and all ligands were favorable for both enzymes, with the ligands interacting even more strongly with AChE, corroborating with IC50 results.