Novel Class of Chalcone Oxime Ethers as Potent Monoamine Oxidase-B and Acetylcholinesterase Inhibitors

Abstract

Previously synthesized novel chalcone oxime ethers (COEs) were evaluated for inhibitory activities against monoamine oxidases (MAOs) and acetylcholinesterase (AChE). Twenty-two of the 24 COEs synthesized, except COE-17 and COE-24, had potent and/or significant selective inhibitory effects on MAO-B. COE-6 potently inhibited MAO-B with an IC50 value of 0.018 µM, which was 105, 2.3, and 1.1 times more potent than clorgyline, lazabemide, and pargyline (reference drugs), respectively. COE-7, and COE-22 were also active against MAO-B, both had an IC50 value of 0.028 µM, which was 67 and 1.5 times lower than those of clorgyline and lazabemide, respectively. Most of the COEs exhibited weak inhibitory effects on MAO-A and AChE. COE-13 most potently inhibited MAO-A (IC50 = 0.88 µM) and also significantly inhibited MAO-B (IC50 = 0.13 µM), and it could be considered as a potential nonselective MAO inhibitor. COE-19 and COE-22 inhibited AChE with IC50 values of 5.35 and 4.39 µM, respectively. The selectivity index (SI) of COE-22 for MAO-B was higher than that of COE-6 (SI = 778.6 vs. 222.2), but the IC50 value (0.028 µM) was slightly lower than that of COE-6 (0.018 µM). In reversibility experiments, inhibitions of MAO-B by COE-6 and COE-22 were recovered to the levels of reference reversible inhibitors and both competitively inhibited MAO-B, with Ki values of 0.0075 and 0.010 µM, respectively. Our results show that COE-6 and COE-22 are potent, selective MAO-B inhibitors, and COE-22 is a candidate of dual-targeting molecule for MAO-B and AChE.

Inhibition of Butyrylcholinesterase by Glycyrol, a Coumarin, Isolated from Glycyrrhiza Uralensis

“…Dual inhibitions of ChE and MAO-B have been investigated in the context of AD [11,16]. In our docking analysis, GC showed greater binding affinity with BChE than with AChE, and LG and liquiritin were predicted to bind to MAO-B more strongly than to MAO-A, and these results agreed well with determined IC50 values.…”

“…Due to the complex etiology of AD, multi-targeting therapeutic agents have been devised to inhibit MAOs and AChE, and thus, elevate monoamine and choline ester levels [11]. Recently, multitargeting agents such as homoisoflavonoid derivatives [12], donepezil-butylated hydroxytoluene hybrids [13], coumarin-dithiocarbamate hybrids [14], alcohol-bearing dual inhibitors [15], and chalcone oxime ethers [16] have been reported to target MAO-B and AChE. Dual function inhibitors of AChE and BChE have been studied using in silico approaches, such as pharmacophore-based virtual screening and molecular docking [17].…”

A New Potent and Selective Monoamine Oxidase‐B Inhibitor with Extended Conjugation in a Chalcone Framework: 1‐[4‐(Morpholin‐4‐yl)phenyl]‐5‐phenylpenta‐2,4‐dien‐1‐one

“…The interactions occurring between MAO-B and MO10, whose styryl group faced the FAD and interacted with Y435, were similar to those already proposed in the published reports, and could be crucial for addressing the inhibition of MAO-B. [43][44][45][46] Conversely, the styryl group did not reach the aromatic cage of MAO-A, made by FAD, Y407 and Y444.…”

Inhibition of Butyrylcholinesterase and Human Monoamine Oxidase-B by the Coumarin Glycyrol and Liquiritigenin Isolated from Glycyrrhiza uralensis

“…Dual inhibitions of ChE and MAO-B have been investigated in the context of AD [ 11 , 16 ]. In the present study, GC potently inhibited BChE with an IC 50 value of 7.22 μM, and moderately inhibited AChE and MAO-B, indicating GC should be considered as a multi-function inhibitor of BChE, AChE, and MAO-B.…”

“…Due to the complex etiology of AD, multi-targeting therapeutic agents have been devised to inhibit MAOs and AChE, and thus, elevate monoamine and choline ester levels [ 11 ]. Recently, multi-targeting agents such as homoisoflavonoid derivatives [ 12 ], donepezil-butylated hydroxytoluene hybrids [ 13 ], coumarin-dithiocarbamate hybrids [ 14 ], alcohol-bearing dual inhibitors [ 15 ], and chalcone oxime ethers [ 16 ] have been reported to target MAO-B and AChE. Dual function inhibitors of AChE and BChE have been studied using in silico approaches, such as pharmacophore-based virtual screening and molecular docking [ 17 ].…”