Acetylcholinesterase and butyrylcholinesterase inhibitory activities of khellactone coumarin derivatives isolated from Peucedanum japonicum Thurnberg.

ABSTRACT: Cholinesterase (ChE) and monoamine oxidase (MAO) inhibitors have been attracted as candidate treatments for Alzheimer's disease (AD). Fifteen khellactone-type coumarins from the roots of Peucedanum japonicum Thunberg were tested for acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and MAO inhibitory activities. Compound 3'-angeloyl-4'-(2-methylbutyryl)khellactone (PJ13) most potently inhibited AChE (IC₅₀?=?9.28 µM), followed by 3'-isovaleryl-4'-(2-methylbutyroyl)khellactone (PJ15) (IC₅₀?=?10.0 ?M). Compound senecioyl-4'-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC₅₀?=?7.22 ?M) and had the highest selectivity index (>?5.54), followed by 3'-senecioyl-4'-(2-methylbutyryl)khellactone (PJ10) and 3',4'-disenecioylkhellactone (PJ4) (IC₅₀?=?10.2 and 10.7 ?M, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with K_i values of 5.98, 10.4 (for AChE), and 4.16 µM (for BChE), respectively. However, all 15 compounds weakly inhibited MAO-A and MAO-B. Molecular docking simulation revealed that PJ13 had a higher binding affinity (-?9.3 kcal/mol) with AChE than PJ15 (-?7.8 kcal/mol) or PJ5 (- 5.4 kcal/mol), due to the formation of a hydrogen bond with Tyr121 (distance: 2.52 Å). On the other hand, the binding affinity of PJ5 (-?10.0 kcal/mol) with BChE was higher than for PJ13 (-?7.7 kcal/mol) or PJ15 (-?8.1 kcal/mol), due to the formation of a hydrogen bond with Ser198 (distance: 2.05 Å). These results suggest that PJ13 and PJ5 are potential reversible selective inhibitors of AChE and BChE, respectively, for the treatment of AD.

SUBMITTER: Heo JH 

PROVIDER: S-EPMC7730441 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature