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 μM). Compound senecioyl-4′-angeloyl-khellactone (PJ5) most potently inhibited BChE (IC50 = 7.22 μM) 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 μM, respectively). Compounds PJ13, PJ15, and PJ5 showed reversible and mixed-types of inhibition with Ki 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.
Highlights
In AD11, and in BChE knockout Alzheimer’s disease (AD) mice, a reported reduction in fibrin Aβ plaque by up to 70% suggests that BChE inhibition has therapeutic v alue[12]
PJ13 and PJ15 resulted in AChE residual activity of < 50% (Table 1)
To examine the multi-targeting abilities of the compounds, we evaluated their inhibitory effects on monoamine oxidase (MAO)-A or MAO-B, which are auxiliary targets in AD
Summary
In AD11, and in BChE knockout AD mice, a reported reduction in fibrin Aβ plaque by up to 70% suggests that BChE inhibition has therapeutic v alue[12]. MAO inhibitors (MAOIs) are currently used to treat depression[22] and Parkinson’s disease[23], and several studies have concluded that MAOIs reduce Aβ p laque[24,25,26], and MAOIs are considered possible future treatments for AD27. An extract of P. japonicum Thunberg (KH020) has been reported to reduce Y-maze alternation behavior, and suggested to have therapeutic value for the prevention and treatment of vascular dementia[35]. We investigated the inhibitory effects of khellactone coumarins from P. japonicum Thunberg on AChE, BChE, and MAOs. In addition, we investigated the bindings and kinetics of the potent inhibitors senecioyl4′-angeloyl-khellactone (PJ5), 3′-angeloyl-4′-(2-methylbutyryl)khellactone (PJ13), and 3′-isovaleryl-4′-(2methylbutyroyl)khellactone (PJ15), and performed molecular docking simulations of these three compounds with AChE and BChE
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