Quercetin and Related Chromenone Derivatives as Monoamine Oxidase Inhibitors: Targeting Neurological and Mental Disorders

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.


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][2][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 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]. 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 ( 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 µM, 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 µM, respectively. However, formononetin exhibited potential inhibitory effect towards MAO-B (IC 50 :11.0 µM) than MAO-A (IC 50 :21.2 µM) [40]. 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][36][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]. 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]. 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  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 µM, respectively and very weak MAO-A inhibitory potential with IC 50 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 (IC 50 < 0.14 and 0.58 µg/mL vs. 1.35 µg/mL), while (−)-epicatechin was found to be more active than Trolox (IC 50 0.14 µg/mL). 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). 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].  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 µM, respectively, while the standard MAO-B inhibitor deprenyl showed an IC 50 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-6-methylether, and scopoletin and were appeared to inhibit MAO with the IC 50    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].
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  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)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)  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 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  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- 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 IC 50 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 (IC 50 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  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].  (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 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]. 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  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  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)  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. 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. 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 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 IC 50 value of the 40 µM. 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)  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. 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 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 MAO-B 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.

5-Hydroxyflavanone and 2-methoxy-
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), Furthermore, the various diglycosides and glycosides of the above-revealed 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].  Furthermore, the various diglycosides and glycosides of the above-revealed 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]. 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 µM respectively, while the other principles showed weak inhibition [58].
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].   (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].

Molecular Docking Studies of Quercetin and Related Flavonoid Derivatives
In  (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]. 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 µM. 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 molecular docking studies by applying the graphical user interface by MacroModel (Maestro GUI), Schrodinger [61]. The interaction energy has shown a good correlation between the exploratory inhibition information and affirmed the particular MAO-A recognition in both configurationally ensembles calculated along with molecular docking and full energy minimization. The authors observed that quercetin associated well within the hMAO-A binding site than in the hMAO-B binding site due to the formation of maximum π-π interaction and intermolecular hydrogen bonds. Moreover Greeson and coauthors also discussed the pharmacological, toxicological, and clinical aspects on MAO inhibitory action of St. John's wort (Hypericum perforatum) [62]. Design of the 3-(4-methoxyphenyl)-1H-benzo[f]chromen-1-one ( Figure 15) was carried out MAO-A inhibitor PDB code (2Z5X) by in-silico techniques [68]. The strategy for the design was to modify the flavanone (C6-C3-C6 three ring skeleton) to benzoflavanone composes naphthalene in spite of the first C6 ring. The binding of this compound with MAO-A was investigated by molecular docking by FlexX program [69]. Visual inspection of the docking poses indicated four more residues, Tyr69, Gly67, Gly443, and Met350 in the complex of 3-(4-methoxyphenyl)-1H-benzo[f]chromen-1-one with MAOA. Moreover, 31 hydrophobic inactions were established with the MAO-A binding cavity.
time than in the hMAO-B pocket.
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 IC50 estimation of 0.010 µM. 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 molecular docking studies by applying the graphical user interface by MacroModel (Maestro GUI), Schrodinger [61]. The interaction energy has shown a good correlation between the exploratory inhibition information and affirmed the particular MAO-A recognition in both configurationally ensembles calculated along with molecular docking and full energy minimization. The authors observed that quercetin associated well within the hMAO-A binding site than in the hMAO-B binding site due to the formation of maximum π-π interaction and intermolecular hydrogen bonds. Moreover Greeson and coauthors also discussed the pharmacological, toxicological, and clinical aspects on MAO inhibitory action of St. John's wort (Hypericum perforatum) [62]. Design of the 3-(4-methoxyphenyl)-1Hbenzo[f]chromen-1-one ( Figure 15) was carried out MAO-A inhibitor PDB code (2Z5X) by in-silico techniques [68]. The strategy for the design was to modify the flavanone (C6-C3-C6 three ring skeleton) to benzoflavanone composes naphthalene in spite of the first C6 ring. The binding of this compound with MAO-A was investigated by molecular docking by FlexX program [69]. Visual inspection of the docking poses indicated four more residues, Tyr69, Gly67, Gly443, and Furthermore, Chimenti et al. [71] reported another series of synthetic flavanones, thioflavones, and flavones, analogs, active against both monoamine oxidase isoforms (MAO-A and -B). To visualize the binding mechanism of both isomers of (R)-2j and (S)-2j enantiomers, docking studies were carried out by the Glide with respect to both isoforms of hMAO [61]. The molecular modeling studies showed good correlations to the experimental results, and hence proved the conformational Furthermore, Chimenti et al. [71] reported another series of synthetic flavanones, thioflavones, and flavones, analogs, active against both monoamine oxidase isoforms (MAO-A and -B). To visualize the binding mechanism of both isomers of (R)-2j and (S)-2j enantiomers, docking studies were carried out by the Glide with respect to both isoforms of hMAO [61]. The molecular modeling studies showed good correlations to the experimental results, and hence proved the conformational flexibility of both 3 dihydrochromen-4-one, 2-(4-fluorophenyl)-7-methyl-2 enantiomers to fit within Furthermore, Chimenti et al. [71] reported another series of synthetic flavanones, thioflavones, and flavones, analogs, active against both monoamine oxidase isoforms (MAO-A and -B). To visualize the binding mechanism of both isomers of (R)-2j and (S)-2j enantiomers, docking studies were carried out by the Glide with respect to both isoforms of hMAO [61]. The molecular modeling studies showed good correlations to the experimental results, and hence proved the conformational flexibility of both 3 dihydrochromen-4-one, 2-(4-fluorophenyl)-7-methyl-2 enantiomers to fit within the active site of both hMAO isoforms with characteristic affinity. The most active compound 2-(4-fluorophenyl)-7-methyl-2,3-dihydrochromen-4-one exhibited nanomolar the inhibitory potential as the racemate and was the most potent inhibitor in the two enantiomeric forms.
More recently Turkmenoglu et al. [72]  Docking experiments showed salvigenin as the most potent hMAO-A inhibitor by forming several van der Waals and electrostatic interactions within the active site of the hMAO-A where aromatic coumarin ring of the salvigenin established two π-π staking with TYR444 and TYR407 residues situated in the cavity. Moreover, the xanthomicrol has shown selective inhibitory interactions towards hMAO-A by forming five hydrogen bonds with the amino acids residues of the side chains of active site hMAO-A isoform (between the hydroxyl and GLY66, hydroxyl and ASN181, hydroxyl and LYS305 and methoxy and TYR444). The aromatic coumarine ring of xanthomicrol was observed sandwiched between the TYR407and TYR444 amino acid residues, which established two π-π interactions with TYR407 and formed a hydrophobic cage within the binding pocket. More relevant molecular binding interactions among the natural leads and hMAO the docked complexes were analyzed by 2-dimensional methods. The docking profile of the selected compounds is given in the ( Table 2).  In a subsequent paper, Gao et al. [63] reported a magnificent in silico target fishing protocol based on mining of diverse database, molecular modeling, ligand similarity searching, structure-based pharmacophore searching and docking protocols together for searching new potential therapeutic anti-Parkinson agents. They concluded that the establishment of productive enzyme-inhibitor interaction behavior of top two ranked targets monoamine oxidase B (MAO-B) and catechol-O-methyltransferase (COMT) from the seven selected protein targets as important targets for baicalein function by literature. For the study flavonoid, baicalein was isolated from the root extract of Scutellaria baicalensis Georgi. Docking calculations were carried out using Glide software for the comparison of binding energy of baicalein with the standard [61]. Two catecholic OH groups of baicalein showed hydrogen bonding with Leu167and Leu164, respectively. Moreover, a network of productive hydrophobic interactions also appeared between MAO-B and baicalein, which appreciably contributed to the binding interactions. Baicalein notably reduced the formation of intracellular NO (nitric oxide), reactive oxygen species, and extracellular NO, due to reduced cell death, exposure of NMDA (N-methyl-D-aspartic acid). It was noticed that NMDA receptor with generally low agreement score cannot be a valuable target for baicalein, having no inhibitory impact on [3H]MK-801 binding. The authors validated and developed a consensus scoring formula for ranking of the targets of a titled compound.
Sivaraman and coworkers performed docking calculations to rationalize the MAO inhibitory potency of luteolin, quercetin, kaempferol, and apigenin by using Auto Dock tools [64]. The binding free energy (∆G) and inhibition constants (Ki) of the natural ligands were computed via the Lamarckian Genetic Algorithm (LGA) of AutoDock application. Perfect to good correlations were established between the experimental and calculated Ki values [73] (Table 3). In a later work, Beula and coworkers [65] isolated 6-prenyl apigenin ( Figure 18) from a methanolic extract of Achyranthes aspera seeds and computed molecular docking to get insight into the binding modes of 6-prenyl apigenin within the monoamine oxidase-A enzyme pocket. Molecular docking studies were carried out by using AutoDock [64], revealed 6-prenyl apigenin as a promising candidate for hMAO-A inhibition by exhibiting calculated inhibition constant of about 1.23 µM and docking score of −8.06. To understand the structural role of the isolated 6-prenyl apigenin the 3D structural was divided into three fragments so-called flavones skeleton, the phenolic group at the 2nd position of the nucleus and a distal side chain located at the 6th position. It is worthy to note that the 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. Furthermore, another π-π stacking interaction has appeared between flavone moiety and TRP 441 residue within the hMAO-A binding site. In a later work, Beula and coworkers [65] isolated 6-prenyl apigenin ( Figure 18) from a methanolic extract of Achyranthes aspera seeds and computed molecular docking to get insight into the binding modes of 6-prenyl apigenin within the monoamine oxidase-A enzyme pocket. Molecular docking studies were carried out by using AutoDock [64], revealed 6-prenyl apigenin as a promising candidate for hMAO-A inhibition by exhibiting calculated inhibition constant of about 1.23 µM and docking score of −8.06. To understand the structural role of the isolated 6-prenyl apigenin the 3D structural was divided into three fragments so-called flavones skeleton, the phenolic group at the 2nd position of the nucleus and a distal side chain located at the 6th position. It is worthy to note that the 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. Furthermore, another π-π stacking interaction has appeared between flavone moiety and TRP 441 residue within the hMAO-A binding site. More recently Zarmouh et al. [74] reported the MAO inhibitory activity of the natural prenylflavanones, genistein (GST) and bavachinin (BNN) from the ethanolic extract of Psoralea corylifolia seeds. Psoralea corylifolia is a medicinal plant widely documented for its antiaging properties. These two unique prenylflavanones selectively inhibited MAO-B enzyme with the highest potential. Docking methodologies predicted the binding affinity for both flavonoids, genistein (GST) and bavachinin (BNN). Zarmouh and coworkers further explored their earlier studies in 2015 [75], the flavanone bavachinin (BNN) and its other structural analog bavachin (BVN) from the seeds of Psoralea corylifolia L. for their human MAO inhibition. Docking studies were performed to validate the correct binding and mechanistic insight into docking poses depicted in (Table 4). The docking poses were analyzed with reference of the bound ligands of the crystal structures of human MAOB-2-(2-benzofuranyl)-2-imidazoline complex and human MAO-A-harmine complex. More recently Zarmouh et al. [74] reported the MAO inhibitory activity of the natural prenylflavanones, genistein (GST) and bavachinin (BNN) from the ethanolic extract of Psoralea corylifolia seeds. Psoralea corylifolia is a medicinal plant widely documented for its antiaging properties. These two unique prenylflavanones selectively inhibited MAO-B enzyme with the highest potential. Docking methodologies predicted the binding affinity for both flavonoids, genistein (GST) and bavachinin (BNN). Zarmouh and coworkers further explored their earlier studies in 2015 [75], the flavanone bavachinin (BNN) and its other structural analog bavachin (BVN) from the seeds of Psoralea corylifolia L. for their human MAO inhibition. Docking studies were performed to validate the correct binding and mechanistic insight into docking poses depicted in (Table 4). The docking poses were analyzed with reference of the bound ligands of the crystal structures of human MAOB-2-(2-benzofuranyl)-2-imidazoline complex and human MAO-A-harmine complex. The same group further studied the isoflavone genistein (GST) and its structural analog daidzein (DZ) as promising MAO-A and MAO-B inhibitors Zarmouh et al. [76]. Molecular docking studies of GST and DZ was performed within the binding pocket of MAO isoforms. In the case of the hMAO-B, both analogs chromone ring were docked entirely within the hydrophobic part of the binding site (substrate-binding domain). Due to their phenolic OH moiety near to the entrance cavity, both derivatives were positioned far from FAD and its surrounding tyrosine amino acid residues. The GST C 4 -OH group moiety formed maximum hydrogen bonds far from the hydrophobic sites than DZ. This molecular network increased the reversibility due to not affecting the flavin structure and possessing reversible H-bond interactions and hydrophobic. In case of MAO-A, the chromone ring of two isoflavone ligands were positioned in the compact entrance cavity near the to the flavin cofactor (FAD), whereas their hydroxy-phenyl group was located to the hydrophobic active site entrance surfaces. Both isoflavones possessed crossed and similar orientation as compared with the standard. A best-matched docking pose of the standard was contributed by a slight pull of GST toward a hydrophilic zone at its C 5 -OH group. The docking studied observations are given in (Table 5). Recently Gidaro and coworkers reported a computational method to generate the binding modes of quercetin and kaempferol to the active site of both hMAO isoforms [66]. All the lowest energy conformations were generated through the application of the OPLS-2005 force field, before docking simulations methods. Computation of free binding energy (∆G Bind) for each docked complex was determined through Prime/MM-GBSA approach along with OPLS-2005 force field and the default parameters settings. Subsequently, quantum mechanics/molecular mechanics (QM/MM) docking calculations were carried out by the Schrödinger QM-Polarized Ligand Docking Protocol (QPLD) application [61]. Finally, results of molecular dynamic simulations established the specificity of the reversible inhibitors was mainly because of the structural shape and size of the substrate/inhibitor cavity, restricted by PHE208 and ILE335 amino acid residues within hMAOA, which correspond to ILE199 and TYR326 in hMAO-B. Binding mode of the kaempferol in the catalytic site of hMAO-A showed hydrophobic interactions with key residues of hMAO-A for a longer time than in the hMAO-B pocket. Kaempferol retained 90% of the simulation time with PHE208 and 80% of the total simulation time hydrophobic interactions with ILE335 of hMAO-A. Conversely, in the binding pocket of hMAO-B, kaempferol retained 80% simulation time with TYR326 and 30% of the simulation time through hydrophobic contacts with ILE199. The detailed description of docking analysis is given in (Table 6).

Conclusions
This deep exploration of the quercetin and related flavonoid derivatives highlights the enthusiasm of therapeutic science specialists towards finding new potent and selective monoamine oxidase inhibitors or useful targeting agents for neurological and mental disorders. The current review is aimed to demonstrate the tremendous pharmacological MAO inhibition profile of natural flavonoid derivatives. The experimental in vitro studies suggested that natural flavonoids showed micro-to nanomolar range IC 50 values against both MAO isoforms. Furthermore, the docking studies correlated in many experiments to explore the molecular mechanism of flavonoid at the MAO receptor level. This may give the idea for the structural activity requirement of different classes of natural flavonoids for the MAO inhibition. Compilation of overall SAR studied indicated some characteristics of flavonoid moiety ( Figure 19). The glycosylation with sugar reduces the hMAO inhibitory potential of flavonoid as studies by Lee and coworkers [50]. Moreover, the mono-substitution enhance the selectivity towards hMAO-A; di-substitution enhance selectivity towards hMAO-B as indicated by Chimenti and coworkers [71]. The unsturation of chromone ring is crucial for MAO inhibition. Nevertheless, Presence of OH group decrease the MAO inhibitory potential as observed by Turkmenoglu and coworkers [72]. Hence, the perditions of in vitro and in silico properties on flavonoid moiety could help to further modification and clinical exploration as flavonoid based potent MAO inhibitors. substrate/inhibitor cavity, restricted by PHE208 and ILE335 amino acid residues within hMAOA, which correspond to ILE199 and TYR326 in hMAO-B. Binding mode of the kaempferol in the catalytic site of hMAO-A showed hydrophobic interactions with key residues of hMAO-A for a longer time than in the hMAO-B pocket. Kaempferol retained 90% of the simulation time with PHE208 and 80% of the total simulation time hydrophobic interactions with ILE335 of hMAO-A. Conversely, in the binding pocket of hMAO-B, kaempferol retained 80% simulation time with TYR326 and 30% of the simulation time through hydrophobic contacts with ILE199. The detailed description of docking analysis is given in (Table 6).

Conclusions
This deep exploration of the quercetin and related flavonoid derivatives highlights the enthusiasm of therapeutic science specialists towards finding new potent and selective monoamine oxidase inhibitors or useful targeting agents for neurological and mental disorders. The current review is aimed to demonstrate the tremendous pharmacological MAO inhibition profile of natural flavonoid derivatives. The experimental in vitro studies suggested that natural flavonoids showed micro-to nanomolar range IC50 values against both MAO isoforms. Furthermore, the docking studies correlated in many experiments to explore the molecular mechanism of flavonoid at the MAO receptor level. This may give the idea for the structural activity requirement of different classes of Figure 19. Structure-activity relationships (SAR) trends inferred from the data of enzymatic and docking experiments reported above.