In Vitro and Molecular Docking Evaluation of the Anticholinesterase and Antidiabetic Effects of Compounds from Terminalia macroptera Guill. & Perr. (Combretaceae)

Abstract

Alzheimer's disease (AD) and diabetes are non-communicable diseases with global impacts. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are suitable therapies for AD, while α-amylase and α-glucosidase inhibitors are employed as antidiabetic agents. Compounds were isolated from the medicinal plant <i>Terminalia macroptera</i> and evaluated for their AChE, BChE, α-amylase, and α-glucosidase inhibitions. From ¹H and ¹³C NMR data, the compounds were identified as 3,3'-di-O-methyl ellagic acid (<b>1</b>), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-xylopyranoside (<b>2</b>), 3,3',4'-tri-O-methyl ellagic acid-4-O-β-D-glucopyranoside (<b>3</b>), 3,3'-di-O-methyl ellagic acid-4-O-β-D-glucopyranoside (<b>4</b>), myricetin-3-O-rhamnoside (<b>5</b>), shikimic acid (<b>6</b>), arjungenin (<b>7</b>), terminolic acid (<b>8</b>), 24-deoxysericoside (<b>9</b>), arjunglucoside I (<b>10</b>), and chebuloside II (<b>11</b>). The derivatives of ellagic acid (<b>1</b>-<b>4</b>) showed moderate to good inhibition of cholinesterases, with the most potent being 3,3'-di-O-methyl ellagic acid, with IC₅₀ values of 46.77 ± 0.90 µg/mL and 50.48 ± 1.10 µg/mL against AChE and BChE, respectively. The compounds exhibited potential inhibition of α-amylase and α-glucosidase, especially the phenolic compounds (<b>1</b>-<b>5</b>). Myricetin-3-O-rhamnoside had the highest α-amylase inhibition with an IC₅₀ value of 65.17 ± 0.43 µg/mL compared to acarbose with an IC₅₀ value of 32.25 ± 0.36 µg/mL. Two compounds, 3,3'-di-O-methyl ellagic acid (IC₅₀ = 74.18 ± 0.29 µg/mL) and myricetin-3-O-rhamnoside (IC₅₀ = 69.02 ± 0.65 µg/mL), were more active than the standard acarbose (IC₅₀ = 87.70 ± 0.68 µg/mL) in the α-glucosidase assay. For α-glucosidase and α-amylase, the molecular docking results for <b>1-11</b> reveal that these compounds may fit well into the binding sites of the target enzymes, establishing stable complexes with negative binding energies in the range of -4.03 to -10.20 kcalmol^-1. Though not all the compounds showed binding affinities with cholinesterases, some had negative binding energies, indicating that the inhibition was thermodynamically favorable.