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

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.

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Monoamine Oxidase Inhibition by Kavalactones from Kava (Piper Methysticum)

Planta Medica ◽

10.1055/a-1008-9491 ◽

2019 ◽

Vol 85 (14/15) ◽

pp. 1136-1142

Author(s):

Denise Prinsloo ◽

Sandra van Dyk ◽

Anél Petzer ◽

Jacobus P. Petzer

Keyword(s):

Enzyme Inhibitor ◽

Dissociation Constants ◽

Piper Methysticum ◽

Experimental Conditions ◽

Mao Inhibitor ◽

Mao B ◽

Mao Inhibition ◽

Mao A ◽

Ic50 Values

AbstractMonoamine oxidases (MAOs) are key metabolic enzymes for neurotransmitter and dietary amines and are targets for the treatment of neuropsychiatric and neurodegenerative disorders. This study examined the MAO inhibition potential of kavain and other kavalactones from the roots of kava (Piper methysticum), a plant that has been used for its anxiolytic properties. (±)-Kavain was found to be a good potency in vitro inhibitor of human MAO-B with an IC50 of 5.34 µM. (±)-Kavain is a weaker MAO-A inhibitor with an IC50 of 19.0 µM. Under the same experimental conditions, the reference MAO inhibitor, curcumin, displays IC50 values of 5.01 µM and 2.55 µM for the inhibition of MAO-A and MAO-B, respectively. It was further established that (±)-kavain interacts reversibly and competitively with MAO-A and MAO-B with enzyme-inhibitor dissociation constants (Ki) of 7.72 and 5.10 µM, respectively. Curcumin in turn, displays a Ki value of 3.08 µM for the inhibition of MAO-A. Based on these findings, other kavalactones (dihydrokavain, methysticin, dihydromethysticin, yangonin, and desmethoxyyangonin) were also evaluated as MAO inhibitors in this study. Yangonin proved to be the most potent MAO inhibitor with IC50 values of 1.29 and 0.085 µM for MAO-A and MAO-B, respectively. It may be concluded that some of the central effects (e.g., anxiolytic) of kava may be mediated by MAO inhibition.

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Design, Synthesis, and Biological Evaluation of Pyridazinones Containing the (2-Fluorophenyl) Piperazine Moiety as Selective MAO-B Inhibitors

Molecules ◽

10.3390/molecules25225371 ◽

2020 ◽

Vol 25 (22) ◽

pp. 5371

Author(s):

Muhammed Çeçen ◽

Jong Min Oh ◽

Zeynep Özdemir ◽

Saliha Ebru Büyüktuncel ◽

Mehtap Uysal ◽

...

Keyword(s):

Biological Evaluation ◽

Inhibitory Potency ◽

Design Synthesis ◽

Docking Simulations ◽

Mao B ◽

Ic50 Value ◽

Competitive Inhibitors ◽

Mao A ◽

Ic50 Values ◽

Synthesis And Biological Evaluation

Twelve pyridazinones (T1–T12) containing the (2-fluorophenyl) piperazine moiety were designed, synthesized, and evaluated for monoamine oxidase (MAO) -A and -B inhibitory activities. T6 was found to be the most potent MAO-B inhibitor with an IC50 value of 0.013 µM, followed by T3 (IC50 = 0.039 µM). Inhibitory potency for MAO-B was more enhanced by meta bromo substitution (T6) than by para bromo substitution (T7). For para substitution, inhibitory potencies for MAO-B were as follows: -Cl (T3) > -N(CH3)2 (T12) > -OCH3 (T9) > Br (T7) > F (T5) > -CH3 (T11) > -H (T1). T6 and T3 efficiently inhibited MAO-A with IC50 values of 1.57 and 4.19 µM and had the highest selectivity indices (SIs) for MAO-B (120.8 and 107.4, respectively). T3 and T6 were found to be reversible and competitive inhibitors of MAO-B with Ki values of 0.014 and 0.0071, respectively. Moreover, T6 was less toxic to healthy fibroblast cells (L929) than T3. Molecular docking simulations with MAO binding sites returned higher docking scores for T6 and T3 with MAO-B than with MAO-A. These results suggest that T3 and T6 are selective, reversible, and competitive inhibitors of MAO-B and should be considered lead candidates for the treatment of neurodegenerative disorders like Alzheimer’s disease.

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Selectivity of Dietary Phenolics for Inhibition of Human Monoamine Oxidases A and B

BioMed Research International ◽

10.1155/2019/8361858 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Zhenxian Zhang ◽

Hiroki Hamada ◽

Phillip M. Gerk

Keyword(s):

Oxidative Stress ◽

Selectivity Index ◽

Cns Disorders ◽

Cardiac Tissues ◽

Monoamine Oxidases ◽

Mao B ◽

Mao A ◽

Ic50 Values ◽

Metabolic Mechanism ◽

Local Levels

Monoamine oxidases (MAOs) regulate local levels of neurotransmitters such as dopamine, norepinephrine, and serotonin and thus have been targeted by drugs for the treatment of certain CNS disorders. However, recent studies have shown that these enzymes are upregulated with age in nervous and cardiac tissues and may be involved in degeneration of these tissues, since their metabolic mechanism releases hydrogen peroxide leading to oxidative stress. Thus, targeting these enzymes may be a potential anti-aging strategy. The purpose of this study was to compare the MAO inhibition and selectivity of selected dietary phenolic compounds, using a previously validated assay that would avoid interference from the compounds. Kynuramine metabolism by human recombinant MAO-A and MAO-B leads to formation of 4-hydroxyquinoline, with Vmax values of 10.2±0.2 and 7.35±0.69 nmol/mg/min, respectively, and Km values of 23.1±0.8 μM and 18.0±2.3 μM, respectively. For oral dosing and interactions with the gastrointestinal tract, curcumin, guaiacol, isoeugenol, pterostilbene, resveratrol, and zingerone were tested at their highest expected luminal concentrations from an oral dose. Each of these significantly inhibited both enzymes except for zingerone, which only inhibited MAO-A. The IC50 values were determined, and selectivity indices (MAO-A/MAO-B IC50 ratios) were calculated. Resveratrol and isoeugenol were selective for MAO-A, with IC50 values of 0.313±0.008 and 3.72±0.20 μM and selectivity indices of 50.5 and 27.4, respectively. Pterostilbene was selective for MAO-B, with IC50 of 0.138±0.013 μM and selectivity index of 0.0103. The inhibition of resveratrol (MAO-A) and pterostilbene (MAO-B) was consistent with competitive time-independent mechanisms. Resveratrol 4’-glucoside was the only compound which inhibited MAO-A, but itself, resveratrol 3-glucoside, and pterostilbene 4’-glucoside failed to inhibit MAO-B. Additional studies are needed to establish the effects of these compounds on MAO-A and/or MAO-B in humans.

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

Molecules ◽

10.3390/molecules25173896 ◽

2020 ◽

Vol 25 (17) ◽

pp. 3896

Author(s):

Geum Seok Jeong ◽

Myung-Gyun Kang ◽

Joon Yeop Lee ◽

Sang Ryong Lee ◽

Daeui Park ◽

...

Keyword(s):

Monoamine Oxidase ◽

Binding Affinity ◽

Competitive Inhibitor ◽

Glycyrrhiza Uralensis ◽

Form Hydrogen Bond ◽

Docking Simulations ◽

Mao B ◽

Mao A ◽

Ic50 Values ◽

Noncompetitive Inhibitor

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. The coumarin glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (>40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (−7.8 kcal/mol) was greater than its affinity for AChE (−7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (−8.8 kcal/mol) was greater than its affinity for MAO-A (−7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

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Development of Halogenated Pyrazolines as Selective Monoamine Oxidase-B Inhibitors: Deciphering via Molecular Dynamics Approach

Molecules ◽

10.3390/molecules26113264 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3264

Author(s):

Aathira Sujathan Nair ◽

Jong-Min Oh ◽

Vishal Payyalot Koyiparambath ◽

Sunil Kumar ◽

Sachithra Thazhathuveedu Sudevan ◽

...

Keyword(s):

Molecular Dynamics ◽

Monoamine Oxidase ◽

Phenyl Ring ◽

Competitive Inhibitor ◽

Selectivity Index ◽

Monoamine Oxidase A ◽

Mao B ◽

Ic50 Value ◽

The Central Nervous System ◽

Inhibitory Activities

Halogens have been reported to play a major role in the inhibition of monoamine oxidase (MAO), relating to diverse cognitive functions of the central nervous system. Pyrazoline/halogenated pyrazolines were investigated for their inhibitory activities against human monoamine oxidase-A and -B. Halogen substitutions on the phenyl ring located at the fifth position of pyrazoline showed potent MAO-B inhibition. Compound 3-(4-ethoxyphenyl)-5-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole (EH7) showed the highest potency against MAO-B with an IC50 value of 0.063 µM. The potencies against MAO-B were increased in the order of –F (in EH7) > –Cl (EH6) > –Br (EH8) > –H (EH1). The residual activities of most compounds for MAO-A were > 50% at 10 µM, except for EH7 and EH8 (IC50 = 8.38 and 4.31 µM, respectively). EH7 showed the highest selectivity index (SI) value of 133.0 for MAO-B, followed by EH6 at > 55.8. EH7 was a reversible and competitive inhibitor of MAO-B in kinetic and reversibility experiments with a Ki value of 0.034 ± 0.0067 µM. The molecular dynamics study documented that EH7 had a good binding affinity and motional movement within the active site with high stability. It was observed by MM-PBSA that the chirality had little effect on the overall binding of EH7 to MAO-B. Thus, EH7 can be employed for the development of lead molecules for the treatment of various neurodegenerative disorders.

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Computationally Assisted Lead Optimization of Novel Potent and Selective MAO-B Inhibitors

Biomedicines ◽

10.3390/biomedicines9101304 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1304

Author(s):

Vedanjali Gogineni ◽

Manal A. Nael ◽

Narayan D. Chaurasiya ◽

Khaled M. Elokely ◽

Christopher R. McCurdy ◽

...

Keyword(s):

Monoamine Oxidase ◽

Methyl Ether ◽

Neurological Disorders ◽

Potential Application ◽

Selectivity Index ◽

Lead Optimization ◽

Mao B ◽

Reversible Inhibition ◽

Mao A ◽

Dietary Flavonoid

A series of dietary flavonoid acacetin 7-O-methyl ether derivatives were computationally designed aiming to improve the selectivity and potency profiles against monoamine oxidase (MAO) B. The designed compounds were evaluated for their potential to inhibit human MAO-A and -B. Compounds 1c, 2c, 3c, and 4c were the most potent with a Ki of 37 to 68 nM against MAO-B. Compounds 1c–4c displayed more than a thousand-fold selectivity index towards MAO-B compared with MAO-A. Moreover, compounds 1c and 2c showed reversible inhibition of MAO-B. These results provide a basis for further studies on the potential application of these modified flavonoids for the treatment of Parkinson’s Disease and other neurological disorders.

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Multifunctional Monoamine Oxidases and Cholinesterases Inhibitory Effects, as well as UPLC-DAD-MS Chemical Profile of Alkaloid Fractions Obtained from Species of the Palicoureeae Tribe

Natural Product Communications ◽

10.1177/1934578x1601100920 ◽

2016 ◽

Vol 11 (9) ◽

pp. 1934578X1601100 ◽

Cited By ~ 2

Author(s):

Luiz Carlos Klein-Júnior ◽

Carolina dos Santos Passos ◽

Juliana Salton ◽

Fernanda Gobbi Bitencourt de ◽

Luís Funez ◽

...

Keyword(s):

Indole Alkaloids ◽

The Other ◽

Chemical Profile ◽

Inhibitory Effects ◽

Pharmacological Activities ◽

Monoamine Oxidases ◽

Mao B ◽

Bche Activity ◽

Neuropsychiatric Diseases ◽

Mao A

In the present study, the effects were evaluated of alkaloid fractions (AFs) from Psychotria species and correlated genera, Palicourea and Rudgea, on monoamine oxidases (MAOs) and cholinesterases (ChEs). By HPLC-DAD and UPLC-DAD-MS analyses, indole alkaloids (IA) were detected in all AFs. For the Psychotria and Palicourea species, these IA corresponded to tetrahydro-β-carboline alkaloids (THβCA). On the other hand, pyrrolidinoindoline core compounds were observed for Rudgea species. Regarding their pharmacological activities, none of the AFs was able to inhibit AChE. However, the BChE activity was impaired by the Psychotria and Palicourea AFs. In addition, MAO-A was inhibited by both AFs, but only Psychotria nemorosa AF was able to inhibit significantly MAO-B. Rudgea AFs demonstrated a poor inhibitory profile on MAO-A. Taken together, our results highlighted the Psychotria and Palicourea genera as important sources of scaffolds for the development of MAO-A and BChE inhibitors aiming at the treatment of neurodegenerative and neuropsychiatric diseases.

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

10.20944/preprints202008.0306.v1 ◽

2020 ◽

Author(s):

Geum Seok Jeong ◽

Myung-Gyun Kang ◽

Joon Yeop Lee ◽

Sang Ryong Lee ◽

Daeui Park ◽

...

Keyword(s):

Binding Affinity ◽

Competitive Inhibitor ◽

Glycyrrhiza Uralensis ◽

Form Hydrogen Bond ◽

Docking Simulations ◽

Mao B ◽

Mao A ◽

Ic50 Values ◽

Noncompetitive Inhibitor ◽

Inhibitory Activities

Eight compounds were isolated from the roots of Glycyrrhiza uralensis and tested for cholinesterase (ChE) and monoamine oxidase (MAO) inhibitory activities. Glycyrol (GC) effectively inhibited butyrylcholinesterase (BChE) and acetylcholinesterase (AChE) with IC50 values of 7.22 and 14.77 µM, respectively, and also moderately inhibited MAO-B (29.48 µM). Six of the other seven compounds only weakly inhibited AChE and BChE, whereas liquiritin apioside moderately inhibited AChE (IC50 = 36.68 µM). Liquiritigenin (LG) potently inhibited MAO-B (IC50 = 0.098 µM) and MAO-A (IC50 = 0.27 µM), and liquiritin, a glycoside of LG, weakly inhibited MAO-B (&gt; 40 µM). GC was a reversible, noncompetitive inhibitor of BChE with a Ki value of 4.47 µM, and LG was a reversible competitive inhibitor of MAO-B with a Ki value of 0.024 µM. Docking simulations showed that the binding affinity of GC for BChE (-7.8 kcal/mol) was greater than its affinity for AChE (-7.1 kcal/mol), and suggested that GC interacted with BChE at Thr284 and Val288 by hydrogen bonds (distances: 2.42 and 1.92 Å, respectively) beyond the ligand binding site of BChE, but that GC did not form hydrogen bond with AChE. The binding affinity of LG for MAO-B (-8.8 kcal/mol) was greater than its affinity for MAO-A (-7.9 kcal/mol). These findings suggest GC and LG should be considered promising compounds for the treatment of Alzheimer’s disease with multi-targeting activities.

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Expression of 5HT-related genes after perinatal treatment with 5HT agonists

Translational Neuroscience ◽

10.2478/s13380-013-0124-3 ◽

2013 ◽

Vol 4 (2) ◽

Cited By ~ 5

Author(s):

Sofia Blažević ◽

Dubravka Hranilović

Keyword(s):

Tryptophan Hydroxylase ◽

Mrna Abundance ◽

Biologically Active ◽

Mrna Levels ◽

Mao Inhibitor ◽

Behavioral Deficits ◽

Mao B ◽

Developmental Disturbances ◽

Mao A ◽

Perinatal Treatment

AbstractSerotonin (5HT) is a biologically active amine with diverse roles in the mammalian organism. Developmental alterations in 5HT homeostasis could lead to exposure of the developing brain to non-optimal serotonin concentrations that may result in developmental and behavioral deficits. In order to explore the molecular basis of the effects of developmental disturbances on 5HT metabolism on adult central 5HT homeostasis, observed in our previous studies, we measured changes in gene expression of the neuronal 5HT-regulating proteins in adult animals after perinatal treatment with the immediate 5HT precursor 5-hydroxytryptophan (5HTP, 25 mg/kg), or monoamine oxidase (MAO) inhibitor tranylcypromine (TCP 2 mg/kg), during the period of the most intensive development of 5HT neurons — from gestational day 12 until postnatal day 21. Adult animals were sacrificed and the relative mRNA levels for tryptophan hydroxylase 2, MAO A, MAO B, receptors 5HT1A and 5HT2A, 5HT transporter (5HTT) and vesicular monoamine transporter (VMAT) were determined in the raphe nuclei region and prefrontal cortex using Real-Time Relative qRT-PCR. In comparison to the saline treated animals, treatment with 5HTP caused mild but significant increase in MAO A and MAO B mRNA abundance. TCP-treated animals, besides an increase in mRNA abundance for both MAO genes, displayed significantly increased 5HTT and VMAT2 mRNA levels and significantly decreased 5HT1A receptor mRNA levels. Our results suggest that perinatal exposure of rats to 5HTP, and especially TCP, induces long-lasting/permanent changes in the expression of 5HT-regulating genes, that presumably underlie 5HT-related neurochemical and behavioral changes in adult animals.

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Ethyl Acetohydroxamate Incorporated Chalcones: Unveiling a Novel Class of Chalcones for Multitarget Monoamine Oxidase-B Inhibitors Against Alzheimer’s Disease

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527318666190906101326 ◽

2019 ◽

Vol 18 (8) ◽

pp. 643-654 ◽

Cited By ~ 11

Author(s):

Reeta ◽

Seung Cheol Baek ◽

Jae Pil Lee ◽

T.M. Rangarajan ◽

Ayushee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Monoamine Oxidase ◽

Target Prediction ◽

Inhibitory Effect ◽

Monoamine Oxidase A ◽

Mao B ◽

Drug Molecules ◽

Ic50 Value ◽

Ic50 Values

Background: Chalcones are considered as the selective scaffold for the inhibition of MAO-B. Objective: A previously synthesized ethyl acetohydroxamate-chalcones (L1-L22) were studied for their inhibitory activities against human recombinant monoamine oxidase A and B (hMAO-A and hMAO-B, respectively) and acetylcholinesterase (AChE) as multi-target directed ligands for the treatment of Alzheimer’s Disease (AD). Methods: Enzyme inhibition studies of MAO-A, MAO-B and AChE is carried out. Computational studies such as Molecular docking, Molecular Mechanics/Generalized Born Surface Area calculations, ADMET prediction, and protein target prediction are also performed. Results: Among the screened compounds, compound L3 has most potent hMAO-B inhibition with an IC50 value of 0.028 ± 0.0016 µM, and other compounds, L1, L2, L4, L8, L12, and L21 showed significant potent hMAO-B inhibition with IC50 values of 0.051 ± 0.0014, 0.086 ± 0.0035, 0.036 ± 0.0011, 0.096 ± 0.0061, 0.083 ± 0.0016, and 0.038 ± 0.0021 µM, respectively. On the other hand, among the tested compounds, compound L13 showed highest hMAO-A inhibition with an IC50 value of 0.51± 0.051 µM and L9 has a significant value of 1.85 ± 0.045 µM. However, the compounds L3 and L4 only showed high selectivities for hMAO-B with Selectivity Index (SI) values of 621.4 and 416.7, respectively. Among the substituents in ring A of ethyl acetohydroxamate-chalcones (L1-L9), F atom at p-position (L3) showed highest inhibitory effect against hMAO-B. This result supports the uniqness and bizarre behavior of fluorine. Moreover, chalcones L3, L4, L9, L11, and L12 showed potential AChE inhibitory effect with IC50 values of 0.67, 0.85, 0.39, 0.30, and 0.45 µM, respectively. Inhibitions of hMAO-B by L3 or L4 were recovered to the level of the reversible reference (lazabemide), and were competitive with Ki values of 0.0030 ± 0.0002 and 0.0046 ± 0.0005 µM, respectively. Inhibitions of AChE by L3 and L11 were of the competitive and mixed types with Ki values of 0.30 ± 0.044 and 0.14 ± 0.0054 µM, respectively. Conclusion: The studies indicated that L3 and L4 are considered to be promising multitarget drug molecules with potent, selective, and reversible competitive inhibitors of hMAO-B and with highly potent AChE inhibitory effect.

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