Quercetin and related chromenone derivatives as monoamine oxidase inhibitors: targeting neurological and mental disorders

molecules Review Quercetin and Related Chromenone Derivatives as Monoamine Oxidase Inhibitors: Targeting Neurological and Mental Disorders Priyanka Dhiman 1, Neelam Malik 1, Eduardo Sobarzo-Sánchez 2,3,*, Eugenio Uriarte 4,5 and Anurag Khatkar 1,* 1Faculty of Pharmaceutical Sciences, M. D. University, Rohtak 124001, India; [email protected] (P.D.); [email protected] (N.M.) 2Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain 3Instituto de Investigación e Innovación en Salud, Facultad de Ciencias de la Salud, Universidad Central de Chile, 8370178 Santiago, Chile 4Departamento de Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain; [email protected] 5Instituto de Ciencias Químicas Aplicadas, Universidad Autónoma de Chile, 7500912 Santiago, Chile *Correspondence: [email protected] (E.S.-S.); [email protected] (A.K.); Tel.: +34-881814887 (E.S.-S.); +91-9671410880 (A.K.) Received: 30 November 2018; Accepted: 22 January 2019; Published: 24 January 2019   Abstract: Monoamine oxidase inhibitions are considered as important targets for the treatment of depression, anxiety, and neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases. This has encouraged many medicinal chemistry research groups for the development of most promising selective monoamine oxidase (MAO) inhibitors. A large number of plant isolates also reported for significant MAO inhibition potential in recent years. Differently substituted flavonoids have been prepared and investigated as MAO-A and MAO-B inhibitors. Flavonoid scaffold showed notable antidepressant and neuroprotective properties as revealed by various and established preclinical trials. The current review made an attempt to summarizing and critically evaluating the new findings on the quercetin and related flavonoid derivatives functions as potent MAO isoform inhibitors. Keywords: monoamine oxidase; neurodegenerative disorder; mental disorders; quercetin; flavonoids; monoamine oxidase inhibitors; in-silico design 1. Introduction Depression and anxiety are estimated as incapacitating mental disorders which impose a huge health burden globally. According to the World Health Organization, major depression has now recognized as the fourth extensive cause of the worldwide in incapacity balanced life-years and could eventually turn into the second most critical cause by 2020 [ 1 – 3 ]. Treatment and therapies for mental disorder are also not economical. In the United States, the expenses of depression treatment and the costs experienced by less research work rate is estimated at more than $44 billion in 1990, which currently raised many fold [ 4 , 5 ]. Hence, the research for the discovery of potent and safe anti-depressant agents has attained importance due to a high mortality ratio of depressive disorders and their contribution for the destruction of other routine physiological processes. Moreover, neurodegenerative disorders constitute the third most essential health issue in different developed countries. Alzheimer’s disease is the most widely recognized neurodegenerative disorder Molecules 2019,24, 418; doi:10.3390/molecules24030418 www.mdpi.com/journal/molecules Molecules 2019,24, 418 2 of 18 followed by Parkinson’s disease. Along with the aging problem of human society, Alzheimer’s disease (AD) has become one of the biggest threats to the modernize population. Alzheimer’s disease is indicated by nerve cells die in the cerebral cortex and accounts for 60 to 80 percent of dementia cases which affected more than 25 million people worldwide in 2000 and may eventually to increase to 114 million by 2050 [ 6 – 9 ]. General treatment of this disease is the utilization of dopaminergic agonists. Nonetheless, other medicinal options can be employed, like the utilization of specific monoamine oxidase B inhibitors, or the use of neuroprotective antioxidant agents to prevent the oxidative damage of neuronal cells. In the last few years, it has been proved that the overexpression of brain MAO-B also causes the neurodegeneration via generation hydroxyl radicals [ 10 , 11 ]. This certainty provokes an increase in free radical generation leads to oxidative stress, neuronal cell death and further the formation of the β-amyloid plaques [12]. The theory of MAO-B inhibitors for the prevention of neuronal damage is also accepted due to the reduction of hydrogen peroxide formation through inhibition of MAO. Clinical data suggests that patients with major depression have symptoms that are reflected changes in brain monoamine neurotransmitters, specifically serotonin (5-HT) and norepinephrine (NE) [ 13 – 15 ]. As per the most accepted hypothesis of depression, including the monoamine theory, dopamine (DA) is also implicated in the pathophysiology of various neurological disorders. Inhibitors of the enzyme monoamine oxidase were the first clinically used antidepressants; however, their utilization has reduced due to their documented serious adverse effects, their drug and food interactions, and the discovery of other target proteins [ 16 – 19 ]. Moreover, reports of hypertensive crises, liver toxicity, and hemorrhages and in some cases death resulted in the withdrawal of many MAO inhibitors from the market. Since then, medicinal chemists have been continuously involved in developing novel lead compounds that can selectively inhibit single isoform of MAO and can act as an effective therapeutic agent for various mental and neurological disorders [20–22]. Monoamine oxidase (MAO; EC 1.4.3.4) is a flavin adenine dinucleotide (FAD) dependent enzyme which is mainly localized on the outer mitochondrial membrane, responsible for the oxidative deamination of monoamines, including neurotransmitters, such as norepinephrine, dopamine, and serotonin (5-hydroxytryptamine [5-HT]) [ 23 , 24 ]. The two isoforms of MAO exists MAO-A and MAO-B, which differ in amino acid sequence, susceptibility to specific inhibitors, substrate specificity, and tissue distribution [ 25 ]. MAO-A preferentially deaminates noradrenaline and serotonin (5-hydroxytryptamine), whereas MAO-B preferentially deaminates β -phenyl-ethylamine and benzylamine. Inside the brain, MAO-B is mainly localized in the glial cells, while MAO-A found in the extraneuronal compartment and inside the dopaminergic, serotonergic and noradrenergic nerve terminals [26]. The oxidative deamination catalyzed through MAO leads to the formation of hydrogen peroxide (H 2 O 2 ) and different reactive oxygen species has sufficient deleterious reactivity which accounts for associated health-related problems including neurological damage. The generation of H 2 O 2 via MAOs is also reported to be a cytotoxic factor involved in oxidative stress, causes degeneration of nigral cells in Parkinson’s disease [27,28]. The modern search in the anti-MAO field is now directed toward the hybrid compounds, the latent risks in bioavailability and safety is a big concern in their further development. Despite notable progress in understanding their isoforms with respect to their 3D-structures, functionality, inhibitors, and substrates, no general rules have been formulated for the rational design of efficient, selective and reversible MAO inhibitors [ 29 , 30 ]. The current review made an attempt to identify the MAO inhibition property of quercetin and related derivatives and establish the rational design of new MAOIs from this investigation. 2. Chemistry and Therapeutic Journey of Quercetin and Related Derivatives Quercetin (3,3 0 ,4 0 ,5,7-pentahydroxyflavone) is the significant illustrative of flavonols, a subclass of flavonoids. Quercetin, a type of flavonoids called flavonols, has received significant consideration in Molecules 2019,24, 418 3 of 18 view of its overwhelming existence in herbs and food [ 31 , 32 ]. The major sources of quercetin are fruits such as citrus, apples, cherries and berries, vegetables such as broccoli, onions, and beverages such as red wine and tea. Moreover, it has been likewise found in several therapeutic plants, for example, Aesculus hippocastanum,Ginkgo biloba, and Hypericum perforatum. Research interest for this flavonol derivative is because of its diverse range of biological properties [33,34]. Quercetin not only shows antioxidant activity like other natural flavonols but is also reported to have antiviral, anti-inflammatory, and antibacterial activities [ 35 – 37 ]. The exact mechanism by which quercetin shows these impacts are not completely clear, but rather it is conceivable that distinctive biochemical procedures are included. This natural flavonol is generally exists in a glycosylated form with its corresponding sugar part, generally glucose. The glycosylation may occur at any of the five OH groups of the flavonol ring, the most widely recognized quercetin glycoside exhibits the sugar moiety and structures speak to 60–75% of flavonoid intake [ 38 ]. Before oral ingestion, quercetin glycosides undergo deglycosylation either by cytosolic β -glucosidase or lactase phlorizin hydrolase. Further, the absorbed aglycone part is conjugated through sulphation, glucuronidation, or methylation. However, the aglycones and associated conjugates can cross the blood-brain barrier. Quercetin consists of a fused ring system with a benzopyran associated with an aromatic ring and phenyl substituents (Figure 1) [39]. Molecules 2019, 24, x 3 of 19 Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is the significant illustrative of flavonols, a subclass of flavonoids. Quercetin, a type of flavonoids called flavonols, has received significant consideration in view of its overwhelming existence in herbs and food [31,32]. The major sources of quercetin are fruits such as citrus, apples, cherries and berries, vegetables such as broccoli, onions, and beverages such as red wine and tea. Moreover, it has been likewise found in several therapeutic plants, for example, Aesculus hippocastanum, Ginkgo biloba, and Hypericum perforatum. Research interest for this flavonol derivative is because of its diverse range of biological properties [33,34]. Quercetin not only shows antioxidant activity like other natural flavonols but is also reported to have antiviral, anti-inflammatory, and antibacterial activities [35–37]. The exact mechanism by which quercetin shows these impacts are not completely clear, but rather it is conceivable that distinctive biochemical procedures are included. This natural flavonol is generally exists in a glycosylated form with its corresponding sugar part, generally glucose. The glycosylation may occur at any of the five OH groups of the flavonol ring, the most widely recognized quercetin glycoside exhibits the sugar moiety and structures speak to 60–75% of flavonoid intake [38]. Before oral ingestion, quercetin glycosides undergo deglycosylation either by cytosolic β-glucosidase or lactase phlorizin hydrolase. Further, the absorbed aglycone part is conjugated through sulphation, glucuronidation, or methylation. However, the aglycones and associated conjugates can cross the blood-brain barrier. Quercetin consists of a fused ring system with a benzopyran associated with an aromatic ring and phenyl substituents (Figure 1) [39]. O O HO OH OH OH OH 1 2' 1' 3' 4' 5' 78 6 5 4 3 26' Figure 1. Quercetin. In a study by Hwang and coworkers raveled the two natural flavonoids from the methanolic root extract of Sophora flavecens. The outcomes of the study indicated the dose-dependent MAO inhibition by kushenol F and formononetin with IC50 values of 69.9 and 13.2 µM, respectively (Figure 2). Interestingly, kushenol F mainly inhibited the MAO-B than MAO-A isoform shown the IC50 values of 63.1 and 103.7 µM, respectively. However, formononetin exhibited potential inhibitory effect towards MAO-B (IC50:11.0 µM) than MAO-A (IC50:21.2 µM) [40]. Figure 2. Structures of Formononetin (1) and Kushenol F (2). In 2010 Samoylenko and coworkers screened Banisteriopsis caapi (Malpighiaceae) constituents for the MAO inhibitory and antioxidative potential (found in South American liana of the family Malpighiaceae, B caapi is known to contain β-carboline alkaloids) [41]. Activity-guided fractionation of aqueous extract of B. caapi stems on led to the isolation of two popular proanthocyanidins (−)- procyanidin B2 and (−)-epicatechin (Figure 3). Epicatechin and (−)-procyanidin B2 showed considerable MAO-B inhibitory activity with IC50 66 and 36 µM, respectively and very weak MAOO OCH3 HO O OHO CH 3 H 2 C H 3 CCH 3 OOH HO OH (1) (2) Figure 1. Quercetin. In a study by Hwang and coworkers raveled the two natural flavonoids from the methanolic root extract of Sophora flavecens. The outcomes of the study indicated the dose-dependent MAO inhibition by kushenol F and formononetin with IC 50 values of 69.9 and 13.2 µ M, respectively (Figure 2). Interestingly, kushenol F mainly inhibited the MAO-B than MAO-A isoform shown the IC 50 values of 63.1 and 103.7 µ M, respectively. However, formononetin exhibited potential inhibitory effect towards MAO-B (IC50:11.0 µM) than MAO-A (IC50:21.2 µM) [40]. Molecules 2019, 24, x 3 of 19 Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is the significant illustrative of flavonols, a subclass of flavonoids. Quercetin, a type of flavonoids called flavonols, has received significant consideration in view of its overwhelming existence in herbs and food [31,32]. The major sources of quercetin are fruits such as citrus, apples, cherries and berries, vegetables such as broccoli, onions, and beverages such as red wine and tea. Moreover, it has been likewise found in several therapeutic plants, for example, Aesculus hippocastanum, Ginkgo biloba, and Hypericum perforatum. Research interest for this flavonol derivative is because of its diverse range of biological properties [33,34]. Quercetin not only shows antioxidant activity like other natural flavonols but is also reported to have antiviral, anti-inflammatory, and antibacterial activities [35–37]. The exact mechanism by which quercetin shows these impacts are not completely clear, but rather it is conceivable that distinctive biochemical procedures are included. This natural flavonol is generally exists in a glycosylated form with its corresponding sugar part, generally glucose. The glycosylation may occur at any of the five OH groups of the flavonol ring, the most widely recognized quercetin glycoside exhibits the sugar moiety and structures speak to 60–75% of flavonoid intake [38]. Before oral ingestion, quercetin glycosides undergo deglycosylation either by cytosolic β-glucosidase or lactase phlorizin hydrolase. Further, the absorbed aglycone part is conjugated through sulphation, glucuronidation, or methylation. However, the aglycones and associated conjugates can cross the blood-brain barrier. Quercetin consists of a fused ring system with a benzopyran associated with an aromatic ring and phenyl substituents (Figure 1) [39]. O O HO OH OH OH OH 1 2' 1' 3' 4' 5' 78 6 5 4 3 26' Figure 1. Quercetin. In a study by Hwang and coworkers raveled the two natural flavonoids from the methanolic root extract of Sophora flavecens. The outcomes of the study indicated the dose-dependent MAO inhibition by kushenol F and formononetin with IC50 values of 69.9 and 13.2 µM, respectively (Figure 2). Interestingly, kushenol F mainly inhibited the MAO-B than MAO-A isoform shown the IC50 values of 63.1 and 103.7 µM, respectively. However, formononetin exhibited potential inhibitory effect towards MAO-B (IC50:11.0 µM) than MAO-A (IC50:21.2 µM) [40]. Figure 2. Structures of Formononetin (1) and Kushenol F (2). In 2010 Samoylenko and coworkers screened Banisteriopsis caapi (Malpighiaceae) constituents for the MAO inhibitory and antioxidative potential (found in South American liana of the family Malpighiaceae, B caapi is known to contain β-carboline alkaloids) [41]. Activity-guided fractionation of aqueous extract of B. caapi stems on led to the isolation of two popular proanthocyanidins (−)- procyanidin B2 and (−)-epicatechin (Figure 3). Epicatechin and (−)-procyanidin B2 showed considerable MAO-B inhibitory activity with IC50 66 and 36 µM, respectively and very weak MAOO OCH3 HO O OHO CH 3 H 2 C H 3 CCH 3 OOH HO OH (1) (2) Figure 2. Structures of Formononetin (1) and Kushenol F (2). In 2010 Samoylenko and coworkers screened Banisteriopsis caapi (Malpighiaceae) constituents for the MAO inhibitory and antioxidative potential (found in South American liana of the family Malpighiaceae, B caapi is known to contain β -carboline alkaloids) [ 41 ]. Activity-guided fractionation of aqueous extract of B. caapi stems on led to the isolation of two popular proanthocyanidins ( − )-procyanidin B2 and ( − )-epicatechin (Figure 3). Epicatechin and ( − )-procyanidin B2 showed considerable MAO-B inhibitory activity with IC 50 66 and 36 µ M, respectively and very weak MAO-A inhibitory potential with IC 50 8.5 and 51.7 µ M for procyanidin B2 and ( − )-epicatechin, respectively. In addition , these components exhibited good antioxidant potential; both found to be more effective than standard antioxidants, vitamin C (IC 50 < 0.14 and 0.58 µ g/mL vs. 1.35 µ g/mL), while (−)-epicatechin was found to be more active than Trolox (IC50 0.14 µg/mL). Molecules 2019,24, 418 4 of 18 Molecules 2019, 24, x 4 of 19 A inhibitory potential with IC50 8.5 and 51.7 µM for procyanidin B2 and (−)-epicatechin, respectively. In addition, these components exhibited good antioxidant potential; both found to be more effective than standard antioxidants, vitamin C (IC50 < 0.14 and 0.58 µg/mL vs. 1.35 µg/mL), while (−)- epicatechin was found to be more active than Trolox (IC50 0.14 µg/mL). Figure 3. Structures of isolated constituents from Banisteriopsis caapi. In another study, the flavan-3-ols (−)-epicatechin and (+)-catechin were isolated from the hook extract of Uncaria rhynchophylla (Miq.) Jacks. using bioguided assay was found to inhibit MAO-B with the IC50 values of 57.9 and 88.9 µM, respectively, while the standard MAO-B inhibitor deprenyl showed an IC50 value of 0.3 µM [42]. (U. rhynchophylla (Rubiaceae), also known as cat’s claw herb, is a rhynchophylline plant species utilized in conventional Chinese medication). Lee et al., isolated flavonoids from 80% watery ethanol concentrate of entire plant of Artemisia vulgaris (Mugwort), and their structures were confirmed by utilizing different spectroscopic techniques. These compounds were recognized as jaceosidin, eupafolin, luteolin, quercetin, apigenin, aesculetin, esculetin-6methylether, and scopoletin and were appeared to inhibit MAO with the IC50 estimations of 19.0, 25.0, 18.5, 72.9, 12.5, 1.0, 31.1, 32.2, and 45.0 µmol, respectively (Figure 4) [43]. O O HO OH HO OH OH OH OH OH OH OH (−)-procyanidin B2 (−)-epicatechin (+)-catechin Figure 3. Structures of isolated constituents from Banisteriopsis caapi. In another study, the flavan-3-ols ( − )-epicatechin and (+)-catechin were isolated from the hook extract of Uncaria rhynchophylla (Miq.) Jacks. using bioguided assay was found to inhibit MAO-B with the IC 50 values of 57.9 and 88.9 µ M, respectively, while the standard MAO-B inhibitor deprenyl showed an IC 50 value of 0.3 µ M [ 42 ]. (U. rhynchophylla (Rubiaceae), also known as cat’s claw herb, is a rhynchophylline plant species utilized in conventional Chinese medication). Lee et al., isolated flavonoids from 80% watery ethanol concentrate of entire plant of Artemisia vulgaris (Mugwort), and their structures were confirmed by utilizing different spectroscopic techniques. These compounds were recognized as jaceosidin, eupafolin, luteolin, quercetin, apigenin, aesculetin, esculetin-6-methylether, and scopoletin and were appeared to inhibit MAO with the IC 50 estimations of 19.0, 25.0, 18.5, 72.9, 12.5, 1.0, 31.1, 32.2, and 45.0 µmol, respectively (Figure 4) [43]. Molecules 2019, 24, x 5 of 19 OHO R 2 OH O R 1 R 4 OR 3 Jaceosidine: R 1 =R 3 =H, R 2 =R 4 =OCH 3 Leuteolin: R 1 =R 2 =R 3 =H,R 4 =OH Apigenin: R 1 =R 2 =R 3 =R 4 =H Eupafolin:R 1 =OH, R 2 =OCH 3 , R 3 =R 4 =H Quercetin: R 1 =R 4 =OH, R 2 =R 3 =H Figure 4. Flavanoids structures description. Conversely, Kim and coworkers isolated a flavonoid, cynaroside from Angelica keiskei Koidzumi (A. keiskei K.). Cynaroside showed notable MAO inhibition with IC50 values MAO-A400 µM and MAO-B 268 µM. Therefore, it is likely that that inhibition of MAO-B exerts antidepressant activity (Figure 5) [44]. O OH O OH OH OGlc Figure 5. Cynaroside. Another study by in 2000 by Pan and coworkers showed the MAO inhibition of isoliquiritigenin and liquiritigenin isolated from the methanolic extract of the flowering plant Sinofranchetia chinensis (Lardizabalaceae) was studied on rodent monoamine oxidase A and B [45]. MAO inhibitory activity was assessed radiochemically by using [14C] β-phenylethylamine (beta-PEA) and [14C]5hydroxytryptamine (5-HT) as MAO-B or -A specific radio labeled substrates, respectively. Isoliquiritigenin and liquiritigenin acted as the potent MAO inhibitors against both MAO-B and -A in a dose-dependent manner (Figure 6). The MAO inhibitory IC50 values were calculated for isoliquiritigenin and liquiritigenin were 14 (12.8–15.6) and 32 (26–36) µmol/L for MAO-A isoform, 47.2 (39.5–54.5) and104.6 (89.0–118.9) µmol/L for MAO-B isoform, respectively. O O OH HO Figure 6. Liquiritigenin. Monoamine oxidase B inhibitory and free radical scavenging activities were evaluated for quercetin, rutin, isoquercitrin, and quercitrin, from the leave isolates of the Melastoma candidum (Melastomataceae) D. Don. using bioassay-guided fractionation (Figure 7) [46]. Melastoma candidum is a Chinese herb reported to clean heat and toxins, activating the blood and eliminating stasis, actuating the blood and wiping out stasis, for treating traumatic wounds, and for enacting Figure 4. Flavanoids structures description. Conversely, Kim and coworkers isolated a flavonoid, cynaroside from Angelica keiskei Koidzumi (A. keiskei K.). Cynaroside showed notable MAO inhibition with IC 50 values MAO-A400 µ M and Molecules 2019,24, 418 5 of 18 MAO-B 268 µ M. Therefore, it is likely that that inhibition of MAO-B exerts antidepressant activity (Figure 5) [44]. Molecules 2019, 24, x 5 of 19 OHO R 2 OH O R 1 R 4 OR 3 Jaceosidine: R 1 =R 3 =H, R 2 =R 4 =OCH 3 Leuteolin: R 1 =R 2 =R 3 =H,R 4 =OH Apigenin: R 1 =R 2 =R 3 =R 4 =H Eupafolin:R 1 =OH, R 2 =OCH 3 , R 3 =R 4 =H Quercetin: R 1 =R 4 =OH, R 2 =R 3 =H Figure 4. Flavanoids structures description. Conversely, Kim and coworkers isolated a flavonoid, cynaroside from Angelica keiskei Koidzumi (A. keiskei K.). Cynaroside showed notable MAO inhibition with IC50 values MAO-A400 µM and MAO-B 268 µM. Therefore, it is likely that that inhibition of MAO-B exerts antidepressant activity (Figure 5) [44]. O OH O OH OH OGlc Figure 5. Cynaroside. Another study by in 2000 by Pan and coworkers showed the MAO inhibition of isoliquiritigenin and liquiritigenin isolated from the methanolic extract of the flowering plant Sinofranchetia chinensis (Lardizabalaceae) was studied on rodent monoamine oxidase A and B [45]. MAO inhibitory activity was assessed radiochemically by using [14C] β-phenylethylamine (beta-PEA) and [14C]5hydroxytryptamine (5-HT) as MAO-B or -A specific radio labeled substrates, respectively. Isoliquiritigenin and liquiritigenin acted as the potent MAO inhibitors against both MAO-B and -A in a dose-dependent manner (Figure 6). The MAO inhibitory IC50 values were calculated for isoliquiritigenin and liquiritigenin were 14 (12.8–15.6) and 32 (26–36) µmol/L for MAO-A isoform, 47.2 (39.5–54.5) and104.6 (89.0–118.9) µmol/L for MAO-B isoform, respectively. O O OH HO Figure 6. Liquiritigenin. Monoamine oxidase B inhibitory and free radical scavenging activities were evaluated for quercetin, rutin, isoquercitrin, and quercitrin, from the leave isolates of the Melastoma candidum (Melastomataceae) D. Don. using bioassay-guided fractionation (Figure 7) [46]. Melastoma candidum is a Chinese herb reported to clean heat and toxins, activating the blood and eliminating stasis, actuating the blood and wiping out stasis, for treating traumatic wounds, and for enacting Figure 5. Cynaroside. Another study by in 2000 by Pan and coworkers showed the MAO inhibition of isoliquiritigenin and liquiritigenin isolated from the methanolic extract of the flowering plant Sinofranchetia chinensis (Lardizabalaceae) was studied on rodent monoamine oxidase A and B [ 45 ]. MAO inhibitory activity was assessed radiochemically by using [14C] β -phenylethylamine (beta-PEA) and [14C]5-hydroxytryptamine (5-HT) as MAO-B or -A specific radio labeled substrates, respectively. Isoliquiritigenin and liquiritigenin acted as the potent MAO inhibitors against both MAO-B and -A in a dose-dependent manner (Figure 6). The MAO inhibitory IC 50 values were calculated for isoliquiritigenin and liquiritigenin were 14 (12.8–15.6) and 32 (26–36) µ mol/L for MAO-A isoform, 47.2 (39.5–54.5) and104.6 (89.0–118.9) µmol/L for MAO-B isoform, respectively. Molecules 2019, 24, x 5 of 19 OHO R 2 OH O R 1 R 4 OR 3 Jaceosidine: R 1 =R 3 =H, R 2 =R 4 =OCH 3 Leuteolin: R 1 =R 2 =R 3 =H,R 4 =OH Apigenin: R 1 =R 2 =R 3 =R 4 =H Eupafolin:R 1 =OH, R 2 =OCH 3 , R 3 =R 4 =H Quercetin: R 1 =R 4 =OH, R 2 =R 3 =H Figure 4. Flavanoids structures description. Conversely, Kim and coworkers isolated a flavonoid, cynaroside from Angelica keiskei Koidzumi (A. keiskei K.). Cynaroside showed notable MAO inhibition with IC50 values MAO-A400 µM and MAO-B 268 µM. Therefore, it is likely that that inhibition of MAO-B exerts antidepressant activity (Figure 5) [44]. O OH O OH OH OGlc Figure 5. Cynaroside. Another study by in 2000 by Pan and coworkers showed the MAO inhibition of isoliquiritigenin and liquiritigenin isolated from the methanolic extract of the flowering plant Sinofranchetia chinensis (Lardizabalaceae) was studied on rodent monoamine oxidase A and B [45]. MAO inhibitory activity was assessed radiochemically by using [14C] β-phenylethylamine (beta-PEA) and [14C]5hydroxytryptamine (5-HT) as MAO-B or -A specific radio labeled substrates, respectively. Isoliquiritigenin and liquiritigenin acted as the potent MAO inhibitors against both MAO-B and -A in a dose-dependent manner (Figure 6). The MAO inhibitory IC50 values were calculated for isoliquiritigenin and liquiritigenin were 14 (12.8–15.6) and 32 (26–36) µmol/L for MAO-A isoform, 47.2 (39.5–54.5) and104.6 (89.0–118.9) µmol/L for MAO-B isoform, respectively. O O OH HO Figure 6. Liquiritigenin. Monoamine oxidase B inhibitory and free radical scavenging activities were evaluated for quercetin, rutin, isoquercitrin, and quercitrin, from the leave isolates of the Melastoma candidum (Melastomataceae) D. Don. using bioassay-guided fractionation (Figure 7) [46]. Melastoma candidum is a Chinese herb reported to clean heat and toxins, activating the blood and eliminating stasis, actuating the blood and wiping out stasis, for treating traumatic wounds, and for enacting Figure 6. Liquiritigenin. Monoamine oxidase B inhibitory and free radical scavenging activities were evaluated for quercetin, rutin, isoquercitrin, and quercitrin, from the leave isolates of the Melastoma candidum (Melastomataceae) D. Don. using bioassay-guided fractionation (Figure 7) [ 46 ]. Melastoma candidum is a Chinese herb reported to clean heat and toxins, activating the blood and eliminating stasis, actuating the blood and wiping out stasis, for treating traumatic wounds, and for enacting fundamental vitality. The IC 50 estimation of the four natural flavonoids, quercetin, rutin, isoquercitrin, and quercitrin on MAO-B was found ass 10.89, 3.89, 11.64, and 19.06 µ M and analysis of enzyme kinetics calculated apparent inhibition constants (Ki) of 7.95, 1.83, 2.72, and 21.01 µM, respectively. Molecules 2019, 24, x 6 of 19 fundamental vitality. The IC50 estimation of the four natural flavonoids, quercetin, rutin, isoquercitrin, and quercitrin on MAO-B was found ass 10.89, 3.89, 11.64, and 19.06 µM and analysis of enzyme kinetics calculated apparent inhibition constants (Ki) of 7.95, 1.83, 2.72, and 21.01 µM, respectively. O OH OH R OOH HO R Compound -O-Glucose Isoquercitrin -O-Rhamnose Quercitrin -O-Glucose -Rhamnose Rutin Figure 7. Structures of flavonoids. The in-vitro MAO inhibition by leaf extract of Ginkgo Biloba was carried out on mouse brain or liver monoamine oxidase (MAO)-A and -B activity [47]. The flavones apigenin and chrysin and the flavonols kaempferol and quercetin were extracted from a validated Gingko biloba preparation by reverse-phase HPLC system. All isolated flavonoid derivatives were observed as selective MAO-A inhibitors with the IC50 estimations of quercetin (4 µM), apigenin (2 µM), kaempferol (0.8 µM), and chrysin (1 µM). In the same assay phenelzine (irreversible and non-selective inhibitor of MAO) was taken as a reference compound (IC50 value 0.05 µM). Quercetin was isolated from the methanolic extract of heather (Calluna vulgaris (L.) Hull– Ericaceae) and was evaluated for MAO inhibition [48]. By exhibiting IC50 value of 18 µM quercetin was distinguished as a selective MAO-A inhibitor. However, clorgyline, an MAO-A selective inhibitor, showed an IC50 value of 0.2 µM in the same assay. Bio-guided fractionation of the Rhodiola rosea L. (Crassulaceae) prompted to the isolation of epigallocatechin gallate (EGCG) dimer (Figure 8) which was tested for MAO inhibition. It showed a sigmoidal dose-response curve for MAO-B with pIC50 of 4.74 µM, whereas l-deprenyl showed the pIC50 value of 7.24 for MAO-B inhibition [49]. O O OH HO HO O HO HO OH OH OH Figure 8. Epigallocatechin gallate. Lee and coworkers isolated different structure analogues of myricetin galloylglycoside from leaves of Acacia confuse, namely myricetin 3-O-(3′′-O-galloyl)-D-rhamnopyranoside (1), myricetin 3O-(2′′-O-galloyl)-D-rhamnopyranoside (2), 3-O-(3′′-O-galloyl)-Drhamnopyranoside 7-methyl ether1(3), myricetin 3-O-(2′′-O-galloyl)-D-rhamnopyranoside 7-methyl ether (4), myricetin 3-O-(2′′, 3′′-di-O-galloyl)-D-rhamnopyranoside (5) (Figure 9). All five derivatives were evaluated for (semicarbazide-sensitive amine oxidase) SSAO inhibition and they all showed considerable amine oxidase inhibitory activity. Notably, the gallic acid at R3 position plays an important role for both biological activities [50]. Figure 7. Structures of flavonoids. The in-vitro MAO inhibition by leaf extract of Ginkgo Biloba was carried out on mouse brain or liver monoamine oxidase (MAO)-A and -B activity [ 47 ]. The flavones apigenin and chrysin and the flavonols kaempferol and quercetin were extracted from a validated Gingko biloba preparation by reverse-phase HPLC system. All isolated flavonoid derivatives were observed as selective MAO-A inhibitors with Molecules 2019,24, 418 6 of 18 the IC 50 estimations of quercetin (4 µ M), apigenin (2 µ M), kaempferol (0.8 µ M), and chrysin (1 µ M). In the same assay phenelzine (irreversible and non-selective inhibitor of MAO) was taken as a reference compound (IC50 value 0.05 µM). Quercetin was isolated from the methanolic extract of heather (Calluna vulgaris (L.) Hull–Ericaceae) and was evaluated for MAO inhibition [ 48 ]. By exhibiting IC 50 value of 18 µ M quercetin was distinguished as a selective MAO-A inhibitor. However, clorgyline, an MAO-A selective inhibitor, showed an IC 50 value of 0.2 µ M in the same assay. Bio-guided fractionation of the Rhodiola rosea L. (Crassulaceae) prompted to the isolation of epigallocatechin gallate (EGCG) dimer (Figure 8) which was tested for MAO inhibition. It showed a sigmoidal dose-response curve for MAO-B with pIC 50 of 4.74 µM, whereas l-deprenyl showed the pIC50 value of 7.24 for MAO-B inhibition [49]. Molecules 2019, 24, x 6 of 19 fundamental vitality. The IC50 estimation of the four natural flavonoids, quercetin, rutin, isoquercitrin, and quercitrin on MAO-B was found ass 10.89, 3.89, 11.64, and 19.06 µM and analysis of enzyme kinetics calculated apparent inhibition constants (Ki) of 7.95, 1.83, 2.72, and 21.01 µM, respectively. O OH OH R OOH HO R Compound -O-Glucose Isoquercitrin -O-Rhamnose Quercitrin -O-Glucose -Rhamnose Rutin Figure 7. Structures of flavonoids. The in-vitro MAO inhibition by leaf extract of Ginkgo Biloba was carried out on mouse brain or liver monoamine oxidase (MAO)-A and -B activity [47]. The flavones apigenin and chrysin and the flavonols kaempferol and quercetin were extracted from a validated Gingko biloba preparation by reverse-phase HPLC system. All isolated flavonoid derivatives were observed as selective MAO-A inhibitors with the IC50 estimations of quercetin (4 µM), apigenin (2 µM), kaempferol (0.8 µM), and chrysin (1 µM). In the same assay phenelzine (irreversible and non-selective inhibitor of MAO) was taken as a reference compound (IC50 value 0.05 µM). Quercetin was isolated from the methanolic extract of heather (Calluna vulgaris (L.) Hull– Ericaceae) and was evaluated for MAO inhibition [48]. By exhibiting IC50 value of 18 µM quercetin was distinguished as a selective MAO-A inhibitor. However, clorgyline, an MAO-A selective inhibitor, showed an IC50 value of 0.2 µM in the same assay. Bio-guided fractionation of the Rhodiola rosea L. (Crassulaceae) prompted to the isolation of epigallocatechin gallate (EGCG) dimer (Figure 8) which was tested for MAO inhibition. It showed a sigmoidal dose-response curve for MAO-B with pIC50 of 4.74 µM, whereas l-deprenyl showed the pIC50 value of 7.24 for MAO-B inhibition [49]. O O OH HO HO O HO HO OH OH OH Figure 8. Epigallocatechin gallate. Lee and coworkers isolated different structure analogues of myricetin galloylglycoside from leaves of Acacia confuse, namely myricetin 3-O-(3′′-O-galloyl)-D-rhamnopyranoside (1), myricetin 3O-(2′′-O-galloyl)-D-rhamnopyranoside (2), 3-O-(3′′-O-galloyl)-Drhamnopyranoside 7-methyl ether1(3), myricetin 3-O-(2′′-O-galloyl)-D-rhamnopyranoside 7-methyl ether (4), myricetin 3-O-(2′′, 3′′-di-O-galloyl)-D-rhamnopyranoside (5) (Figure 9). All five derivatives were evaluated for (semicarbazide-sensitive amine oxidase) SSAO inhibition and they all showed considerable amine oxidase inhibitory activity. Notably, the gallic acid at R3 position plays an important role for both biological activities [50]. Figure 8. Epigallocatechin gallate. Lee and coworkers isolated different structure analogues of myricetin galloylglycoside from leaves of Acacia confuse, namely myricetin 3-O-(3”-O-galloyl)-D-rhamnopyranoside ( 1 ), myricetin 3-O-(2”-O-galloyl)-D-rhamnopyranoside ( 2 ), 3-O-(3”-O-galloyl)-Drhamnopyranoside 7-methyl ether1( 3 ), myricetin 3-O-(2”-O-galloyl)-D-rhamnopyranoside 7-methyl ether ( 4 ), myricetin 3-O-(2”, 3”-di-O-galloyl)-D-rhamnopyranoside ( 5 ) (Figure 9). All five derivatives were evaluated for (semicarbazide-sensitive amine oxidase) SSAO inhibition and they all showed considerable amine oxidase inhibitory activity. Notably, the gallic acid at R 3 position plays an important role for both biological activities [50]. Molecules 2019, 24, x 7 of 19 O OH OR 1 OH OH OH O O OH OH R 2 OR 3 O Compound R 1 R 2 R 3 1 H H Galloyl 2 H Galloyl H 3 CH 3 H Galloyl 4 CH 3 Galloyl H 5 H Galloyl Galloyl Figure 9. Structure description of myricetin galloylglycosides. The neurological and neuroprotective properties of Melissa officinalis was also documented by Lopez and coworkers. They assessed MAO-A inhibitory potential of methanolic extract of Melissa officinalis the plant. The IC50 estimations for MAO-A by methanolic extract (19.3 ± 2.3) was found to be better than the aqueous extract (48.3 ± 5.7) [51]. The antidepressant action of Morinda citrifolia fruit extracts was evaluated by estimation of MAO inhibition studies [52]. The bioactivity-fractionation led two flavonoids, quercetin, and kaempferol. Bioassay of kaempferol (Figure 10) and quercetin, for MAO-A, calculated IC50 values of 3.15 M and 0.72 M, and 20.4 M and 31.7 M for MAO-B, respectively, selectivity indices for MAO-A shown as 28 and 10. O O HO H OH OH OH Figure 10. Kaempferol. Isolation of kaempferol and apigenin flavonoids from Sophorae flos and demonstration of their strong MAO-A inhibitory effects over rat brain mitochondrial monoamine oxidase MAO-A with an IC50 estimation of 10, and 14 µM were carried out by Ryu and coworkers [53]. They concluded that both compounds do not preferentially inhibit MAO-B. Moreover, several other isoflavonoids were isolated from Glycine max. and screened. In which the genistein (Figure 11) selectively inhibited rat brain mitochondrial MAO-A with IC50 value of the 40 µM. OOH HO O OH Figure 11. Genistein. Naringenin (Figure 12) was collected from the ethanolic extract of Mentha aquatica L. via by bioactivity-guided fractionation on preparative TLC [54]. The MAO inhibitory IC50 values by naringenin were calculated as 340 ± 30 M for the homogenate of rat liver mitochondrial fraction, 288 ± 18 M was calculated for MAO-B and for MAO-A 955 ± 129 M. However the MAO inhibitory potential of was not more than quercetin. Figure 9. Structure description of myricetin galloylglycosides. The neurological and neuroprotective properties of Melissa officinalis was also documented by Lopez and coworkers. They assessed MAO-A inhibitory potential of methanolic extract of Melissa officinalis the plant. The IC 50 estimations for MAO-A by methanolic extract (19.3 ± 2.3) was found to be better than the aqueous extract (48.3 ± 5.7) [ 51 ]. The antidepressant action of Morinda citrifolia fruit extracts was evaluated by estimation of MAO inhibition studies [ 52 ]. The bioactivity-fractionation led two flavonoids, quercetin, and kaempferol. Bioassay of kaempferol (Figure 10) and quercetin, Molecules 2019,24, 418 7 of 18 for MAO-A , calculated IC 50 values of 3.15 M and 0.72 M, and 20.4 M and 31.7 M for MAO-B, respectively, selectivity indices for MAO-A shown as 28 and 10. Molecules 2019, 24, x 7 of 19 O OH OR 1 OH OH OH O O OH OH R 2 OR 3 O Compound R 1 R 2 R 3 1 H H Galloyl 2 H Galloyl H 3 CH 3 H Galloyl 4 CH 3 Galloyl H 5 H Galloyl Galloyl Figure 9. Structure description of myricetin galloylglycosides. The neurological and neuroprotective properties of Melissa officinalis was also documented by Lopez and coworkers. They assessed MAO-A inhibitory potential of methanolic extract of Melissa officinalis the plant. The IC50 estimations for MAO-A by methanolic extract (19.3 ± 2.3) was found to be better than the aqueous extract (48.3 ± 5.7) [51]. The antidepressant action of Morinda citrifolia fruit extracts was evaluated by estimation of MAO inhibition studies [52]. The bioactivity-fractionation led two flavonoids, quercetin, and kaempferol. Bioassay of kaempferol (Figure 10) and quercetin, for MAO-A, calculated IC50 values of 3.15 M and 0.72 M, and 20.4 M and 31.7 M for MAO-B, respectively, selectivity indices for MAO-A shown as 28 and 10. O O HO H OH OH OH Figure 10. Kaempferol. Isolation of kaempferol and apigenin flavonoids from Sophorae flos and demonstration of their strong MAO-A inhibitory effects over rat brain mitochondrial monoamine oxidase MAO-A with an IC50 estimation of 10, and 14 µM were carried out by Ryu and coworkers [53]. They concluded that both compounds do not preferentially inhibit MAO-B. Moreover, several other isoflavonoids were isolated from Glycine max. and screened. In which the genistein (Figure 11) selectively inhibited rat brain mitochondrial MAO-A with IC50 value of the 40 µM. OOH HO O OH Figure 11. Genistein. Naringenin (Figure 12) was collected from the ethanolic extract of Mentha aquatica L. via by bioactivity-guided fractionation on preparative TLC [54]. The MAO inhibitory IC50 values by naringenin were calculated as 340 ± 30 M for the homogenate of rat liver mitochondrial fraction, 288 ± 18 M was calculated for MAO-B and for MAO-A 955 ± 129 M. However the MAO inhibitory potential of was not more than quercetin. Figure 10. Kaempferol. Isolation of kaempferol and apigenin flavonoids from Sophorae flos and demonstration of their strong MAO-A inhibitory effects over rat brain mitochondrial monoamine oxidase MAO-A with an IC 50 estimation of 10, and 14 µ M were carried out by Ryu and coworkers [ 53 ]. They concluded that both compounds do not preferentially inhibit MAO-B. Moreover, several other isoflavonoids were isolated from Glycine max. and screened. In which the genistein (Figure 11) selectively inhibited rat brain mitochondrial MAO-A with IC50 value of the 40 µM. Molecules 2019, 24, x 7 of 19 O OH OR 1 OH OH OH O O OH OH R 2 OR 3 O Compound R 1 R 2 R 3 1 H H Galloyl 2 H Galloyl H 3 CH 3 H Galloyl 4 CH 3 Galloyl H 5 H Galloyl Galloyl Figure 9. Structure description of myricetin galloylglycosides. The neurological and neuroprotective properties of Melissa officinalis was also documented by Lopez and coworkers. They assessed MAO-A inhibitory potential of methanolic extract of Melissa officinalis the plant. The IC50 estimations for MAO-A by methanolic extract (19.3 ± 2.3) was found to be better than the aqueous extract (48.3 ± 5.7) [51]. The antidepressant action of Morinda citrifolia fruit extracts was evaluated by estimation of MAO inhibition studies [52]. The bioactivity-fractionation led two flavonoids, quercetin, and kaempferol. Bioassay of kaempferol (Figure 10) and quercetin, for MAO-A, calculated IC50 values of 3.15 M and 0.72 M, and 20.4 M and 31.7 M for MAO-B, respectively, selectivity indices for MAO-A shown as 28 and 10. O O HO H OH OH OH Figure 10. Kaempferol. Isolation of kaempferol and apigenin flavonoids from Sophorae flos and demonstration of their strong MAO-A inhibitory effects over rat brain mitochondrial monoamine oxidase MAO-A with an IC50 estimation of 10, and 14 µM were carried out by Ryu and coworkers [53]. They concluded that both compounds do not preferentially inhibit MAO-B. Moreover, several other isoflavonoids were isolated from Glycine max. and screened. In which the genistein (Figure 11) selectively inhibited rat brain mitochondrial MAO-A with IC50 value of the 40 µM. OOH HO O OH Figure 11. Genistein. Naringenin (Figure 12) was collected from the ethanolic extract of Mentha aquatica L. via by bioactivity-guided fractionation on preparative TLC [54]. The MAO inhibitory IC50 values by naringenin were calculated as 340 ± 30 M for the homogenate of rat liver mitochondrial fraction, 288 ± 18 M was calculated for MAO-B and for MAO-A 955 ± 129 M. However the MAO inhibitory potential of was not more than quercetin. Figure 11. Genistein. Naringenin (Figure 12) was collected from the ethanolic extract of Mentha aquatica L. via by bioactivity-guided fractionation on preparative TLC [ 54 ]. The MAO inhibitory IC 50 values by naringenin were calculated as 340 ± 30 M for the homogenate of rat liver mitochondrial fraction, 288 ±18 M was calculated for MAO-B and for MAO-A 955 ± 129 M. However the MAO inhibitory potential of was not more than quercetin. Molecules 2019, 24, x 8 of 19 OHO OH O OH Figure 12. Naringenin. 5-Hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6one (Figure 13) were extracted from the dried bark methanolic concentrate of Gentiana lutea [55]. Monoamine oxidase activity was evaluated on rat brain mitochondria fraction. Compound 2methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one specifically inhibited MAOB isoform, whereas entire inhibition was observed at 9 µM. 5-hydroxyflavanone exhibited more affinity for MAO for MAO-B than MAO-A isoform. Enzyme kinetics for the MAO inhibition was carried out by Lineweaver-Burk plots and both compounds showed the reciprocal plot curves for MAO inhibition activities, where the concentration of substrate also found intersected to the ordinate. The apparent Ki values of compounds of 5-hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)- 6a,10a-dihydrobenzo(1,2-c)chroman-6-one for MAO-B were calculated as 1.1 µM and 1.4 µM, respectively. In another study MAO inhibition studies were performed on pure anthocyanidins and the MAO-A and MAO-B inhibitory IC50 values were calculated as for pelargonidin (28 µM and 45 µM), peonidin (41 µM and 25 µM), malvidin (32 µM and 20 µM), delphinidin (36 µM and 38 µM), cyanidin (31 µM and 33 µM), and petunidin (35 µM and 45 µM). Figure 13. Structures of 5-hydroxyflavanone (3) and 2-methoxy-3-(1-dimethylallyl)-6a,10adihydrobenzo(1,2-c)chroman-6-one (4). Furthermore, the various diglycosides and glycosides of the aboverevealed anthocyanidins were also investigated for MAO inhibition with IC50 estimation of 30–120 µM against MAO-A and 32–247 µM against MAO-B [56]. Bioactivity-guided isolation of seven flavonoids from the methanolic extract of Cayratia japonica was carried out to evaluate MAO inhibitory potential [57]. The structures of the components were identified as apigenin, apigenin-7-O-β-D-glucuronopyranoside, quercetin, luteolin, (+)-dihydrokaempferol (aromadendrin), (+)-dihydroquercetin (taxifolin), and luteolin-7-O-β-D-glucopyranoside. Among the all titled compounds, flavonol, quercetin as well as the flavones such as luteolin and apigenin showed potential MAO inhibitory effects with estimated IC50 values of 33.7 µM, 23.7 and 6.7 respectively. Furthermore, quercetin was found as most active MAO-A inhibitor (IC50 value: 1 µM) than MAO-B (IC50 value: 90 µM), whereas luteolin and apigenin also mainly inhibited MAO-A isoform (IC50 values: 5 .0and 1.0 µM, respectively) as compared with MAO-B (IC50 values: 60.0 and 13.0 µM, respectively). Moreover, the flavanonol derivatives, aromadendrin, and taxifolin exhibited poor inhibition (IC50 values: 152.9 µM and 155.1, respectively). The flavone glycosides, luteolin-7-Oβ-D-glucopyranoside and apigenin-7-O-β-D-glucuronopyranoside exhibited less MAO inhibitory activity (IC50 values: 118.6 and 81.7 µM, respectively). (3) (4) O H 3 CO CH 2 O Figure 12. Naringenin. 5-Hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one (Figure 13) were extracted from the dried bark methanolic concentrate of Gentiana lutea [ 55 ]. Monoamine oxidase activity was evaluated on rat brain mitochondria fraction. Compound 2-methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one specifically inhibited MAO-B isoform, whereas entire inhibition was observed at 9 µ M. 5-hydroxyflavanone exhibited more affinity for MAO for MAO-B than MAO-A isoform. Enzyme kinetics for the MAO inhibition was carried out by Lineweaver-Burk plots and both compounds showed the reciprocal plot curves for MAO inhibition activities, where the concentration of substrate also found intersected to the ordinate. The apparent Ki values of compounds of 5-hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one for MAO-B were calculated as 1.1 µM and 1.4 µM, respectively. Molecules 2019,24, 418 8 of 18 Molecules 2019, 24, x 8 of 19 OHO OH O OH Figure 12. Naringenin. 5-Hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6one (Figure 13) were extracted from the dried bark methanolic concentrate of Gentiana lutea [55]. Monoamine oxidase activity was evaluated on rat brain mitochondria fraction. Compound 2methoxy-3-(1-dimethylallyl)-6a,10a-dihydrobenzo(1,2-c)chroman-6-one specifically inhibited MAOB isoform, whereas entire inhibition was observed at 9 µM. 5-hydroxyflavanone exhibited more affinity for MAO for MAO-B than MAO-A isoform. Enzyme kinetics for the MAO inhibition was carried out by Lineweaver-Burk plots and both compounds showed the reciprocal plot curves for MAO inhibition activities, where the concentration of substrate also found intersected to the ordinate. The apparent Ki values of compounds of 5-hydroxyflavanone and 2-methoxy-3-(1-dimethylallyl)- 6a,10a-dihydrobenzo(1,2-c)chroman-6-one for MAO-B were calculated as 1.1 µM and 1.4 µM, respectively. In another study MAO inhibition studies were performed on pure anthocyanidins and the MAO-A and MAO-B inhibitory IC50 values were calculated as for pelargonidin (28 µM and 45 µM), Figure 13. Structures of 5-hydroxyflavanone (3) and 2-methoxy-3-(1-dimethylallyl)-6a,10adihydrobenzo(1,2-c)chroman-6-one (4). Furthermore, the various diglycosides and glycosides of the aboverevealed anthocyanidins were also investigated for MAO inhibition with IC50 estimation of 30–120 µM against MAO-A and 32–247 µM against MAO-B [56]. Bioactivity-guided isolation of seven flavonoids from the methanolic extract of Cayratia japonica was carried out to evaluate MAO inhibitory potential [57]. The structures of the components were identified as apigenin, apigenin-7-O-β-D-glucuronopyranoside, quercetin, luteolin, (+)-dihydrokaempferol (aromadendrin), (+)-dihydroquercetin (taxifolin), and luteolin-7-O-β-D-glucopyranoside. Among the all titled compounds, flavonol, quercetin as well as the flavones such as luteolin and apigenin showed potential MAO inhibitory effects with estimated IC50 values of 33.7 µM, 23.7 and 6.7 respectively. Furthermore, quercetin was found as most active MAO-A inhibitor (IC50 value: 1 µM) than MAO-B (IC50 value: 90 µM), whereas luteolin and apigenin also mainly inhibited MAO-A isoform (IC50 values: 5 .0and 1.0 µM, respectively) as compared with MAO-B (IC50 values: 60.0 and 13.0 µM, respectively). Moreover, the flavanonol derivatives, aromadendrin, and taxifolin exhibited poor inhibition (IC50 values: 152.9 µM and 155.1, respectively). The flavone glycosides, luteolin-7-Oβ-D-glucopyranoside and apigenin-7-O-β-D-glucuronopyranoside exhibited less MAO inhibitory activity (IC50 values: 118.6 and 81.7 µM, respectively). (3) (4) O H 3 CO CH 2 O Figure 13. Structures of 5-hydroxyflavanone ( 3 ) and 2-methoxy-3-(1-dimethylallyl)-6a,10adihydrobenzo(1,2-c)chroman-6-one (4). In another study MAO inhibition studies were performed on pure anthocyanidins and the MAO-A and MAO-B inhibitory IC 50 values were calculated as for pelargonidin (28 µ M and 45 µ M), peonidin (41 µ M and 25 µ M), malvidin (32 µ M and 20 µ M), delphinidin (36 µ M and 38 µ M), cyanidin (31 µ M and 33 µM), and petunidin (35 µM and 45 µM). Furthermore, the various diglycosides and glycosides of the aboverevealed anthocyanidins were also investigated for MAO inhibition with IC 50 estimation of 30–120 µM against MAO-A and 32–247 µM against MAO-B [56]. Bioactivity-guided isolation of seven flavonoids from the methanolic extract of Cayratia japonica was carried out to evaluate MAO inhibitory potential [ 57 ]. The structures of the components were identified as apigenin, apigenin-7-Oβ -D-glucuronopyranoside, quercetin, luteolin, (+)-dihydro-kaempferol (aromadendrin), (+)-dihydroquercetin (taxifolin), and luteolin-7-Oβ -D-glucopyranoside. Among the all titled compounds, flavonol, quercetin as well as the flavones such as luteolin and apigenin showed potential MAO inhibitory effects with estimated IC 50 values of 33.7 µ M, 23.7 and 6.7 respectively. Furthermore, quercetin was found as most active MAO-A inhibitor (IC 50 value: 1 µ M) than MAO-B (IC 50 value: 90 µ M), whereas luteolin and apigenin also mainly inhibited MAO-A isoform (IC 50 values: 5.0 and 1.0 µ M, respectively) as compared with MAO-B (IC 50 values: 60.0 and 13.0 µ M, respectively). Moreover, the flavanonol derivatives, aromadendrin, and taxifolin exhibited poor inhibition (IC50 values: 152.9 µ M and 155.1, respectively). The flavone glycosides, luteolin-7-Oβ -D-glucopyranoside and apigenin-7-Oβ -D-glucuronopyranoside exhibited less MAO inhibitory activity (IC 50 values: 118.6 and 81.7 µM, respectively). Fourteen types of herbal plants were evaluated for MAO-B inhibitory potential. The extracts of Chrysanthemum indicum,Sophora japonica,Artemisia Messer-Schmidtiana,Ericibe obtusifolis significantly inhibited the MAO-B enzyme. Among them, Chrysanthemi indicum was selected for fractionation and identification of its active components, which led some flavonoids as diosmetin, acacetin, apigenin, 5,7-dihydroxy chromone, luteolin, and eriodictyol. The MAO inhibitory IC 50 values for 5,7-dihydroxy chromone and diosmetin were calculated as following: 2.50, 0.20, 2.10 µ M respectively, while the other principles showed weak inhibition [58]. Isoflavone daidzein and its various analogs such as daidzin, ononin, 7-oω -carboxypentylflavone, 7-O-r-carboxyheptyldaidzein, 7-o-isopropyldaidzein, 7-o-dodecyldaidzein, 7-oω -carboxyheptyldaidzein, 7-oω -carboxyundecyldaidzein, 7-oω -hydroxyethyl-2-(2-oxyethyl) oxyethyldaidzein (Figure 14) were evaluated for MAO inhibition. It was concluded that presence of a free 4 0 -OH function on isoflavone ring and a straight 7-O-alkyl chain substitution, that has a terminal polar function such as -COOH, -OH, and -NH 2 is crucial for MAO inhibition. Most preferable chain lengths for the MAO inhibition were 7-O-ω-hydroxy, 7-O-ω-carboxy, and 7-O-ω-amino substituent, were respectively [59]. Molecules 2019,24, 418 9 of 18 Molecules 2019, 24, x 9 of 19 Fourteen types of herbal plants were evaluated for MAO-B inhibitory potential. The extracts of Chrysanthemum indicum, Sophora japonica, Artemisia Messer-Schmidtiana, Ericibe obtusifolis significantly inhibited the MAO-B enzyme. Among them, Chrysanthemi indicum was selected for fractionation and identification of its active components, which led some flavonoids as diosmetin, acacetin, apigenin, 5,7-dihydroxy chromone, luteolin, and eriodictyol. The MAO inhibitory IC50 values for 5,7-dihydroxy chromone and diosmetin were calculated as following: 2.50, 0.20, 2.10 µM respectively, while the other principles showed weak inhibition [58]. Figure 14. Chemical structures of isoflavone daidzein and its various analogs. Isoflavone daidzein and its various analogs such as daidzin, ononin, 7-o-ωcarboxypentylflavone, 7-O-r-carboxyheptyldaidzein, 7-o-isopropyldaidzein, 7-o-dodecyldaidzein, 7o-ω-carboxyheptyldaidzein, 7-o-ω-carboxyundecyldaidzein, 7-o-ω-hydroxyethyl-2-(2-oxyethyl) oxyethyldaidzein (Figure 14) were evaluated for MAO inhibition. It was concluded that presence of a free 4′-OH function on isoflavone ring and a straight 7-O-alkyl chain substitution, that has a terminal polar function such as -COOH, -OH, and -NH2 is crucial for MAO inhibition. Most preferable chain lengths for the MAO inhibition were 7-O-ω-hydroxy, 7-O-ω-carboxy, and 7-O-ω-amino substituent, were respectively [59]. 3. Molecular Docking Studies of Quercetin and Related Flavonoid Derivatives In 2006, Zhang et al. determined MAO inhibition of natural flavonoids by docking experiments. Docking methodologies revealed that the quercetin can thoroughly bind within the active site of the hMAO-B (with drug score of −61.5). Close inspection of the docking poses shown that the binding not only depends on the hydroxyl groups at 7th or 5th positions (that is equivalent to the positions 1st and 3rd in xanthone ring) but also on the OHs present at other positions (Table 1). Furthermore, the ring B in catechol seems very important which notably contributes for the binding, and could increase the MAO inhibiting capacity of quercetin. This special character of OH and ring B found unique as compared to xanthones, which do not require catechol for the better restricting association with MAO protein and can be justified to some degree by the more adaptability of flavonoids than xanthones. This may because of the ring B in flavonoids that is rotatable through C2-C10 bond, through so the flavonoids modify their conformational changes to tie inside the dynamic locales of MAO proteins, pictured by the superimposed quercetin adaptations in the coupling pocket of MAOB [60]. Table 1. Docking profile of natural flavonoids with target protein and interactions. Flavonoids Target Protein Important Amino Acid Residues Comments Software References O OOH Glc O OOH HO O OOCH 3 Glc Daidzin Daidzein Ononin O O HO OH O O HO 7 4'-dihydroxyflavone 7-hydroxyflavone Figure 14. Chemical structures of isoflavone daidzein and its various analogs. 3. Molecular Docking Studies of Quercetin and Related Flavonoid Derivatives In 2006, Zhang et al. determined MAO inhibition of natural flavonoids by docking experiments. Docking methodologies revealed that the quercetin can thoroughly bind within the active site of the hMAO-B (with drug score of − 61.5). Close inspection of the docking poses shown that the binding not only depends on the hydroxyl groups at 7th or 5th positions (that is equivalent to the positions 1st and 3rd in xanthone ring) but also on the OHs present at other positions (Table 1). Furthermore, the ring B in catechol seems very important which notably contributes for the binding, and could increase the MAO inhibiting capacity of quercetin. This special character of OH and ring B found unique as compared to xanthones, which do not require catechol for the better restricting association with MAO protein and can be justified to some degree by the more adaptability of flavonoids than xanthones. This may because of the ring B in flavonoids that is rotatable through C2-C10 bond, through so the flavonoids modify their conformational changes to tie inside the dynamic locales of MAO proteins, pictured by the superimposed quercetin adaptations in the coupling pocket of MAO-B [60]. Table 1. Docking profile of natural flavonoids with target protein and interactions. Flavonoids Target Protein Important Amino Acid Residues Comments Software References Quercetin MAO-A PDB (2Z5X) Tyr444, Tyr197, and Asn181 Quercetin fitted well within the hMAO-A active site than in the hMAO-B active site due to development of highest π-π interaction and intermolecular hydrogen bonds. Schrodinger [61] Zhang et al. [62] Baicalein MAO-B PDB (2Z5Y) Leu164 and Leu167 Two catecholic OH groups of baicalein showed hydrogen bonding with Leu167and Leu164 respectively. Schrodinger [61] Gao et al. [63] 6-prenyl apigenin hMAO-A PDB (2Z5X) Tyr 444 and Tyr407 6-prenyl apigenin the structural shared π electrons of the hydroxyl groups were sandwiched between phenolic side chains of TYR407 and TYR 444 composed the ‘aromatic cage’ of the hydrophobic pocket of the enzyme. AutoDock [64] Beula et al. [65] Kaempferol hMAO-A PDB (2Z5X) Ile335 of hMAO-A Tyr326 of hMAO-B Kaempferol in the dynamic site of hMAO-A established hydrophobic interactions with important residues of hMAO-A for a longer time than in the hMAO-B pocket. Schrödinger [61] Gidaro et al. [66] The methanolic extract from leaves of Hypericum hircinum showed monoamine oxidases (MAO) inhibition. The bioactivity guided isolation prompted to the isolation of quercetin and five different components, recognized for the first time from H. hircinum [ 67 ]. Quercetin was the main compound with a specific inhibitory action against MAO-A, with an IC 50 estimation of 0.010 µ M. To illustrate the behavioral impacts of quercetin the in-vivo animal study on mice was performed using the forced swimming test. The mechanism of inhibition was further confirmed by Molecules 2019,24, 418 16 of 18 21. McCabe-Sellers, B.J.; Staggs, C.G.; Bogle, M.L. Tyramine in foods and monoamine oxidase inhibitor drugs: A crossroad where medicine, nutrition, pharmacy, and food industry converge. J. Food. Compost. Anal. 2006 , 19, 58–65. [CrossRef] 22. Rapaport, M.H. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: The state of the art. J. Clin. Psychiatry. 2007,68, 42–46. [PubMed] 23. Shih, J.C.; Chen, K.; Ridd, M.J. Monoamine oxidase: From genes to behavior. Annu. Rev. Neurosci. 1999 ,22, 197–198. [CrossRef] 24. Ebadi, M.; Brown-Borg, H.; Ren, J.; Sharma, S.; Shavali, S.; El ReFaey, H.; Carlson, E.C. Therapeutic efficacy of selegiline in neurodegenerative disorders and neurological diseases. Curr. Drug. Targets. 2006 ,7, 1513–1529. [CrossRef] [PubMed] 25. Kalgutkar, A.S.; Dalvie, D.K.; Castagnoli, N.; Taylor, T.J. Interactions of nitrogen-containing xenobiotics with monoamine oxidase (MAO) isozymes A and B: SAR studies on MAO substrates and inhibitors. Chem. Res. Toxicol. 2001,14, 1139–1162. [CrossRef] [PubMed] 26. Carradori, S.; Silvestri, R. New Frontiers in Selective Human MAO-B Inhibitors: Miniperspective. J. Med. Chem. 2015,58, 6717–6732. [CrossRef] 27. Maurel, A.; Hernandez, C.; Kunduzova, O.; Bompart, G.; Cambon, C.; Parini, A.; Francés, B. Age-dependent increase in hydrogen peroxide production by cardiac monoamine oxidase A in rats. Am. J. Physiol. Heart. Circ. Physiol. 2003,284, 1460–1470. [CrossRef] 28. Maker, H.S.; Weiss, C.; Silides, D.J.; Cohen, G. Coupling of dopamine oxidation (monoamine oxidase activity) to glutathione oxidation via the generation of hydrogen peroxide in rat brain homogenates. J. neurochem. 1981,36, 589–593. [CrossRef] 29. Ji, H.F.; Zhang, H.Y. Multipotent natural agents to combat Alzheimer’s disease. Functional spectrum and structural features. Acta. Pharmacol. Sin. 2008,29, 143–151. [CrossRef] 30. Decker, M. Hybrid molecules incorporating natural products: Applications in cancer therapy, neurodegenerative disorders and beyond. Curr. Med. Chem. 2011,18, 1464–1475. [CrossRef] 31. Erlund, I. Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutr. Res. 2004,24, 851–874. [CrossRef] 32. Nijveldt, R.J.; Van Nood, E.L.; Van Hoorn, D.E.; Boelens, P.G.; Van Norren, K.; Van Leeuwen, P.A. Flavonoids: A review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr. 2001 ,74, 418–425. [CrossRef] [PubMed] 33. Proteggente, A.R.; Pannala, A.S.; Paganga, G.; Buren, L.V.; Wagner, E.; Wiseman, S.; Put, F.V.; Dacombe, C.; Rice-Evans, C.A. The antioxidant activity of regularly consumed fruit and vegetables reflects their phenolic and Vitamin C composition. Free. Radic. Res. 2002,36, 217–233. [CrossRef] [PubMed] 34. Hirpara, K.V.; Aggarwal, P.; Mukherjee, A.J.; Joshi, N.; Burman, A.C. Quercetin and its derivatives: Synthesis, pharmacological uses with special emphasis on anti-tumor properties and prodrug with enhanced bio-availability. Anticancer. Agents. Med. Chem. 2009,9, 138–161. [CrossRef] [PubMed] 35. Guardia, T.; Rotelli, A.E.; Juarez, A.O.; Pelzer, L.E. Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat. II farmaco. 2001,56, 683–687. [CrossRef] 36. Bravo, A.; Anacona, J.R. Metal complexes of the flavonoid quercetin: Antibacterial properties. Transit. Metal. Chem. 2001,26, 20–23. [CrossRef] 37. Kaul, T.N.; Middleton, E.; Ogra, P.L. Antiviral effect of flavonoids on human viruses. J. Med. Virol. 1985 ,15, 71–79. [CrossRef] [PubMed] 38. Ververidis, F.; Trantas, E.; Douglas, C.; Vollmer, G.; Kretzschmar, G.; Panopoulos, N. Biotechnology of flavonoids and other phenylpropanoid-derived natural products. Part I: Chemical diversity, impacts on plant biology and human health. Biotechnol. J. 2007,2, 1214–1234. [CrossRef] [PubMed] 39. Jäger, A.K.; Saaby, L. Flavonoids and the CNS. Molecules 2011,16, 1471–1485. [CrossRef] [PubMed] 40. Hwang, J.S.; Lee, S.A.; Hong, S.S.; Lee, K.S.; Lee, M.K.; Hwang, B.Y.; Ro, J.S. Monoamine oxidase inhibitory components from the roots of Sophora flavescens. Arch. Pharm. Res. 2005 ,28, 190–194. [CrossRef] [PubMed] 41. Samoylenko, V.; Rahman, M.M.; Tekwani, B.L.; Tripathi, L.M.; Wang, Y.H.; Khan, S.I.; Khan, I.A.; Miller, L.S.; Joshi, V.C.; Muhammad, I. Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson’s disease. J. Ethnopharmacol. 2010,127, 357–367. [CrossRef] [PubMed] Molecules 2019,24, 418 17 of 18 42. Hou, W.C.; Lin, R.D.; Chen, C.T.; Lee, M.H. Monoamine oxidase B (MAO-B) inhibition by active principles from Uncaria rhynchophylla. J. Ethnopharmacol. 2005,100, 216–220. [CrossRef] [PubMed] 43. Lee, S.J.; Chung, H.Y.; Lee, I.K.; Oh, S.U.; Yoo, I.D. Phenolics with inhibitory activity on mouse brain monoamine oxidase (MAO) from whole parts of Artemisia vulgaris L (Mugwort). Food. Sci. Biotechnol. 2000 , 9, 179–182. 44. Kim, J.H.; Son, Y.K.; Kim, G.H.; Hwang, K.H. Xanthoangelol and 4-hydroxyderricin are the major active principles of the inhibitory activities against monoamine oxidases on Angelica keiskei K. Biomol. Ther. 2013 , 21, 234–235. [CrossRef] 45. Pan, X.; Kong, L.D.; Zhang, Y.; Cheng, C.H.; Tan, R.X. In vitro inhibition of rat monoamine oxidase by liquiritigenin and isoliquiritigenin isolated from Sinofranchetia chinensis. Acta. Pharmacol. Sin. 2000 ,21, 949–953. 46. Lee, M.H.; Lin, R.D.; Shen, L.Y.; Yang, L.L.; Yen, K.Y.; Hou, W.C. Monoamine oxidase B and free radical scavenging activities of natural flavonoids in Melastoma candidum D. Don. J. Agric. Food Chem. 2001 ,49, 5551–5555. [CrossRef] 47. Sloley, B.D.; Urichuk, L.J.; Morley, P.; Durkin, J.; Shan, J.J.; Pang, P.K.; Coutts, R.T. Identification of kaempferol as a monoamine oxidase inhibitor and potential neuroprotectant in extracts of Ginkgo biloba leaves. J. Pharm. Pharmacol. 2000,52, 451–459. [CrossRef] 48. Saaby, L.; Rasmussen, H.B.; Jäger, A.K. MAO-A inhibitory activity of quercetin from Calluna vulgaris (L.) Hull. J. Ethnopharmacol. 2009,121, 178–181. [CrossRef] 49. Van Diermen, D.; Marston, A.; Bravo, J.; Reist, M.; Carrupt, P.A.; Hostettmann, K. Monoamine oxidase inhibition by Rhodiola rosea L. roots. J. Ethnopharmacol. 2009,122, 397–401. [CrossRef] 50. Lee, T.H.; Liu, D.Z.; Hsu, F.L.; Wu, W.C.; Hou, W.C. Structure-activity relationships of five myricetin galloylglycosides from leaves of Acacia confusa. Bot. Stud. 2006,47, 37–43. 51. López, V.; Martín, S.; Gómez-Serranillos, M.P.; Carretero, M.E.; Jäger, A.K.; Calvo, M.I. Neuroprotective and neurological properties of Melissa officinalis. Neurochem. Res. 2009,34, 1955–1961. [CrossRef] [PubMed] 52. Deng, S.; West, B.J. Antidepressant effects of noni fruit and its active principals. Asian. J. Med. Sci. 2011 ,3, 79–83. 53. Ryu, S.Y.; Han, Y.N.; Han, B.H. Monoamine oxidase-A inhibitors from medicinal plants. Arch. Pharm. Res. 1988,11, 230–239. [CrossRef] 54. Olsen, H.T.; Stafford, G.I.; van Staden, J.; Christensen, S.B.; Jäger, A.K. Isolation of the MAO-inhibitor naringenin from Mentha aquatica L. J. Ethnopharmacol. 2008,117, 500–502. [CrossRef] [PubMed] 55. Haraguchi, H.; Tanaka, Y.; Kabbash, A.; Fujioka, T.; Ishizu, T.; Yagi, A. Monoamine oxidase inhibitors from Gentiana lutea. Phytochemistry 2004,65, 2255–2260. [CrossRef] [PubMed] 56. Dreiseitel, A.; Korte, G.; Schreier, P.; Oehme, A.; Locher, S.; Domani, M.; Hajak, G.; Sand, P.G. Berry anthocyanins and their aglycons inhibit monoamine oxidases A and B. Pharmacol. Res. 2009 ,59, 306–311. [CrossRef] [PubMed] 57. Han, X.H.; Hong, S.S.; Hwang, J.S.; Lee, M.K.; Hwang, B.Y.; Ro, J.S. Monoamine oxidase inhibitory components from Cayratia japonica. Arch. Pharm. Res. 2007,30, 13–70. [CrossRef] [PubMed] 58. Han, Y.N.; Noh, D.B.; Han, D.S. Studies on the monoamine oxidase inhibitors of medicinal plants I. Isolation of MAO-B inhibitors from Chrysanthemum indicum. Arch. Pharm. Res. 1987,10, 142–147. [CrossRef] 59. Gao, G.Y.; Li, D.J.; Keung, W.M. Synthesis of potential antidipsotropic isoflavones: Inhibitors of the mitochondrial monoamine oxidase-aldehyde dehydrogenase pathway. J. Med. Chem. 2001 ,44, 3320–3328. [CrossRef] [PubMed] 60. Ji, H.F.; Zhang, H.Y. Theoretical evaluation of flavonoids as multipotent agents to combat Alzheimer’s disease. J. Mol. Struct. Theochem. 2006,767, 3–9. [CrossRef] 61. Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; et al. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy. J. Med. Chem. 2004,47, 1739–1749. [CrossRef] [PubMed] 62. Greeson, J.M.; Sanford, B.; Monti, D.A. St. John’s wort (Hypericum perforatum): A review of the current pharmacological, toxicological, and clinical literature. Psychopharmacology 2001 ,153, 402–414. [CrossRef] [PubMed] Molecules 2019,24, 418 18 of 18 63. Gao, L.; Fang, J.S.; Bai, X.Y.; Zhou, D.; Wang, Y.T.; Liu, A.L.; Du, G.H. In silico Target Fishing for the Potential Targets and Molecular Mechanisms of Baicalein as an Antiparkinsonian Agent: Discovery of the Protective Effects on NMDA Receptor-Mediated Neurotoxicity. Chem. Biol. Drug. Des. 2013 ,81, 675–687. [CrossRef] [PubMed] 64. Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem. 2009 ,30, 2785–2791. [CrossRef] [PubMed] 65. Beula, S.J.; Raj, V.B.; Mathew, B. Isolation and molecular recognization of 6-prenyl apigenin towards MAO-A as the active principle of seeds of Achyranthes aspera. Biomed. Prev. Nutr. 2014,4, 379–382. [CrossRef] 66. Gidaro, M.C.; Astorino, C.; Petzer, A.; Carradori, S.; Alcaro, F.; Costa, G.; Artese, A.; Rafele, G.; Russo, F.M.; Petzer, J.P.; et al. Kaempferol as selective human MAO-A inhibitor: analytical detection in calabrian red wines, biological and molecular modeling studies. J. Agric. Food Chem. 2016 ,64, 1394–1400. [CrossRef] [PubMed] 67. Chimenti, F.; Cottiglia, F.; Bonsignore, L.; Casu, L.; Casu, M.; Floris, C.; Secci, D.; Bolasco, A.; Chimenti, P.; Granese, A.; et al. Quercetin as the Active Principle of Hypericum h ircinum Exerts a Selective Inhibitory Activity against MAO-A: Extraction, Biological Analysis, and Computational Study. J. Nat. Prod. 2006 ,69, 945–949. [CrossRef] [PubMed] 68. Jo, G.; Sung, S.H.; Lee, Y.; Kim, B.G.; Yoon, J.; Lee, H.O.; Ji, S.Y.; Koh, D.; Ahn, J.H.; Lim, Y. Discovery of Monoamine Oxidase A Inhibitors Derived from in silico Docking. Bull. Korean. Chem. Soc. 2012 ,33, 3841–3844. [CrossRef] 69. Rarey, M.; Kramer, B.; Lengauer, T.; Klebe, G. A fast flexible docking method using an incremental construction algorithm. J. Mol. Biol. 1996,261, 470–489. [CrossRef] 70. Desideri, N.; Bolasco, A.; Fioravanti, R.; Proietti, M.L.; Orallo, F.; Yáñez, M.; Ortuso, F.; Alcaro, S. Homoisoflavonoids: Natural scaffolds with potent and selective monoamine oxidase-B inhibition properties. J. Med. Chem. 2011,54, 2155–2164. [CrossRef] 71. Chimenti, F.; Fioravanti, R.; Bolasco, A.; Chimenti, P.; Secci, D.; Rossi, F.; Yáñez, M.; Orallo, F.; Ortuso, F.; Alcaro, S.; et al. A new series of flavones, thioflavones, and flavanones as selective monoamine oxidase-B inhibitors. Bioorg. Med. Chem. 2010,18, 1273–1279. [CrossRef] [PubMed] 72. Turkmenoglu, F.P.; Baysal, ˙ I.; Ciftci-Yabanoglu, S.; Yelekci, K.; Temel, H.; Pa¸sa, S.; Ezer, N.; Çalı¸s, ˙ I.; Ucar, G. Flavonoids from Sideritis species: Human monoamine oxidase (hMAO) inhibitory activities, molecular docking studies and crystal structure of xanthomicrol. Molecules 2015,20, 7454–7473. [CrossRef] [PubMed] 73. Sivaraman, D.; Vignesh, G.; Selvaraj, R.; Dare, B.J. Identification of potential monoamine oxidase inhibitor from herbal source for the treatment of major depressive disorder: An in-silico screening approach. Der. Pharma. Chemica. 2015,7, 224–234. 74. Zarmouh, N.; Eyunni, S.; Mazzio, E.; Messeha, S.; Elshami, F.; Soliman, K. Bavachinin and Genistein, Two Novel Human Monoamine Oxidase-B (MAO-B) Inhibitors in the Psoralea Corylifolia Seeds. FASEB J. 2015 , 29, 771–772. 75. Zarmouh, N.O.; Mazzio, E.A.; Elshami, F.M.; Messeha, S.S.; Eyunni, S.V.; Soliman, K.F. Evaluation of the inhibitory effects of bavachinin and bavachin on human monoamine oxidases A and B. Evid. Based. Complement. Alternat. Med. 2015, 1–14. [CrossRef] [PubMed] 76. Zarmouh, N.O.; Messeha, S.S.; Elshami, F.M.; Soliman, K.F. Evaluation of the Isoflavone Genistein as Reversible Human Monoamine Oxidase-A and-B Inhibitor. Evid. Based. Complement. Alternat. Med. 2016 , 1–12. [CrossRef] [PubMed] © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).