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Plant Secondary Metabolites- Potent Inhibitors of Monoamine Oxidase Isoforms Bijo Mathew1*, Jerad Suresh2, Githa Elizabeth Mathew3, R. Parasuraman1 and N. Abdulla4 1
Division of Drug Design & Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad 678004, Kerala, India; 2Department of Pharmaceutical Chemistry, Madras Medical College, Chennai-600003, India; 3Department of Pharmacology, Grace College of Pharmacy, Palakkad 678004, Kerala, India; 4Department of Pharmaceutical Chemistry, Malik Deenar College of Pharmacy, Kasaragod 671321, Kerala, India Abstract: Target of monoamine oxidase inhibitions are considered as the treatment of depressive states and neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. Many medicinal chemistry research groups are actively working in this area for the development of most promising selective MAO inhibitors. Many plant isolates also showed remarkable MAO inhibition in recent years. The objective of this review is to identify the major MAO inhibitors secondary metabolites from plants like flavonoids, alkaloids and xanthones class of compounds.
Keywords: Alkaloids, flavonoids, monoamine oxidase inhibitors, xanthones. INTRODUCTION Monoamine oxidase (MAO) is a flavin-adenosine dinucleotide (FAD) depending enzyme and mainly localized on the outer mitochondrial membrane of mammalian brain and peripheral tissues. The primary role of MAO connected with the regulation of neurotransmitter level and degradation of dietary amines [1]. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is crucial for the regulation of emotional and other brain functions in the central nervous system. The development of human MAO inhibitors (MAOIs) led to an important turning point in the therapy of several neuropsychiatric and neurodegenerative disorders [2]. Depending upon the substrate specificity and sensitivity, MAO enzymes are exist as two isoforms, MAO-A and MAO-B. The main function of MAOIs is blocking the enzyme metabolism and developing an increase availability of biogenic amines for their physiological functions. MAOA preferentially deaminate serotonin, epinephrine and norepinephrine and MAO-B metabolizes benzyl amine and β-phenylethylamine, dopamine, tyramine and tryotamine are common substrates for both MAO isoforms [3]. In the last decade, a huge number of research work has been connected with the field of MAOIs by identifying the crystallographic structures of both isoforms [4-6]. Human MAO-A inhibitors are used as antidepressants and antianxiety agents and human MAO-B inhibitors are used alone or in combination in the therapy of Alzheimer’s disease and Parkinson’s disease [7-10]. To inhibit the inhibitor binding *Address correspondence to this author at the Division of Drug Design & Medicinal Chemistry Research Lab, Department of Pharmaceutical Chemistry, Grace College of Pharmacy, Palakkad 678004, Kerala, India; Tel: +91 9946700219; Fax: 0491 2508537; E-mail:
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cavity (IBC) of MAO-A, fundamental element is the N5 charge transfer bond of the isoalloxazine nucleus of FAD, while to MAO-B inhibition, molecule lipophilicity is important [11]. Many synthetic derivatives like pyrazoline, coumarin, hexahydroindazole, caffeine, thiazole, anilide, indole, quinoxaline, thiomorphine and benzafuran showed remarkable activity towards the inhibition of MAO isoforms in recent years [12-25]. MONOAMINE OXIDASE INHIBITION OF ISOLATED PLANT METABOLITES Apart from the synthetic derivatives, isolated plant metabolites also exhibited remarkable inhibition activity towards both isoforms of MAO. The current review made an attempt to identify the MAO inhibition property of important secondary plant metabolites like flavonoids, alkaloids and xanthones from the plant source and establish the rational design of new MAOIs from this investigation. FLAVONOIDS AS THE SOURCE FOR MAO INHIBITION Han et al. isolated some flavonoids such acacetin, apigenin, diosmetin, eriodictyol and luteolin from Chrysanthemum indicum and screened for their MAO-B inhibition. Their research revealed that the flavonoids acacetin and diosmetin showed good inhibitory action towards rat liver mitochondrial monoamine oxidase MAO-B with an IC50 value of 2.46 and 2.11mM respectively (Fig. 1, 2) [26]. Ryu et al. isolated apigenin and kaempferol flavonoids from Sophorae flos and showed strong inhibitory effects towards rat brain mitochondrial monoamine oxidase MAO-A with an IC50 value of 10µM (Fig. 3, 4). Their research highlighted that both compounds do not inhibit MAO-B. In addition they also isolated some isoflavonoids from Glycine © 2014 Bentham Science Publishers
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max. In that genistein (Fig. 5) showed inhibitory effects towards rat brain mitochondrial monoamine oxidase MAO-A with an IC50 value of 40µM [27]. Haraguchi et al. isolated 5hydroxyflavanone (Fig. 6) from Gentiana lutea showed an IC50 value of 39.6 and 3.8 µM towards both rat brain mitochondrial monoamine oxidase MAO-A and B respectively. They concluded that an increase in MAO-B inhibition activity increases brain levels of hydroxy radical which can protect the brain tissues against oxidative stress [28].
Fig. (1).
Fig. (2).
Fig. (3).
Fig. (4).
Fig. (5).
Mathew et al.
Fig. (6).
Sloley et al. isolated kaempferol, apigenin and chrysin from leaves of Ginkgo biloba proved to be potent MAOIs, but produced more pronounced inhibition of MAO-A than MAO-B. They claimed that inhibition of MAO by these related flavone compounds appears to be dependent on the presence of a phenyl or hydroxyphenyl ring in the 2 position and a double bond in the 2, 3 position of the favonoid nucleus [29]. Hou et al. isolated known compounds like (+)catechin and (−)-epicatechin from Uncaria rhynchophylla, a Chinese herbal drug that is generally used to treat convulsive disorders. Their research showed that (+)-catechin and (−)epicatechin showed good inhibitory action towards wistar rat brain mitochondrial monoamine oxidase MAO-B with an IC50 value of 88.6 and 58.9µM respectively. The inhibition occurred in a dose-dependent manner which was measured by the fluorescence method [30]. Hwang et al. isolated two known flavonoids such as formononetin and kushenol from the methanol extracts of the roots of Sophora flavescens. Formononetin (Fig. 7) showed a slightly more potent inhibitory effect against mouse brain mitochondrial monoamine oxidase MAO-B (IC50= 11.0 µM) than MAO-A (IC50= 21.2 µM). Kushenol (Fig. 8) also showed more inhibitory effect against mouse brain mitochondrial monoamine oxidase MAO-B than MAO-A with an IC50 value of 63.1 and 103.7 µM respectively [31]. Chimenti et al. isolated quercetin from the methanol extract of Hypericum hircinum leaves. It is interesting to pointing out that quercetin showed a selective inhibitory activity against beef brain mitochondrial monoamine oxidase MAO-A with an IC50 value of 0.010 µM (Fig. 9). They also carried out a computational study to justify the selective inhibition of the MAO-A enzyme. The molecular docking revealed that quercetin fits better in the hMAO-A than in the hMAO-B cleft, with more intermolecular hydrogen bonds and π-π stacking interaction. During the docking of quercetin, 3ʹ-OH group of B ring, 3-OH group of C ring and 5-H group of A ring established hydrogen bonding with Glu216, Asn 181 and Tyr197 respectively. The non-planar nature of B ring of quercetin helped the position of phenyl system of A-ring to make a π-π stacking interaction with phenyl unit of Tyr407 and Tyr444. At this configuration, FAD molecule is appeared to a close proximity towards the A ring of quercetin [32]. Han et al. isolated some flavonoids from the whole plant and fruits of Cayratia japonica .The order of inhibitory potency of the isolated compounds against MAO activity is shown as follows: flavone flavonol> flavone glycoside> flavanonol. In this series apigenin showed inhibitory effects towards mouse brain mitochondrial monoamine oxidase MAO-A with an IC50 value of 1.17µM. It was observed that level of MAO inhibitory activity decreased with increasing
Plant Secondary Metabolites- Potent Inhibitors of Monoamine
hydroxy groups in the B ring of flavone [33]. Olsen et al. isolated naringenin from ethanol extract of Mentha aquatica and evaluated their invitro inhibitory effect of MAO-A and B. The IC50 values for MAO inhibition by naringenin were 342±33 µM for the rat liver mitochondrial fraction, 955±129µM for MAO-A and 288±18µM for MAO-B (Fig. 10). On the basis of the reported literature of the ability of naringenin to cross the blood-brain barrier, they concluded that the isolated compound can enter into the CNS and can use the treatment of depression-like conditions [34, 35]. Saaby et al. isolated quercetin from methanol extract of Calluna vulgaris and tested in a photometric peroxidase linked MAO-A bioassay and the IC50 value was found to be 18±0.2 µM. The result of quercetin IC50 value towards MAO-A in the previous studies of Chimenti and Han et al. showed to be 0.01 and 2.8 µM respectively. This controversial observation found in the previous literature was justified by Sabby et al. and claimed a fact that, it is difficult to compare the IC50- values reported for the flavonoids, as assay conditions vary and not all studies give IC50-values for standard compounds [36].
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STRUCTURE ACTIVITY RELATIONSHIP OF (SAR) FLAVONOIDS TOWARDS MAO On the basis of inhibitory action of flavonoids towards MAO isoenzymes, the following are the general SAR principles are established. •
Selectivity of the inhibition of MAO isoforms by flavonoidal class of compound mainly depends upon the substituents present in the B ring and double bond present in the 2 and 3 position of C ring.
•
The presence of electron donating lipophilic methoxyl group in the para position of B ring favours the MAO-B inhibition.
•
The presence of electron donating hydrophilic hydroxyl group in the para position of B ring favours the MAO-A inhibition.
•
Shifting of B ring of hydroxyl phenyl group from second to third position of C ring reduces MAO-B inhibitory activity.
•
The absence of double bond between 2 and 3 position of the C ring maintains the non-planar nature of flavonoids. This feature appreciably selective towards MAO-B inhibition.
ALKALOIDS AS THE SOURCE FOR MAO INHIBITION Fig. (7).
Fig. (8).
Kong et al. isolated three protoberberine alkaloids like jatrorrhizine, berberine and palmatine from the methanol extract of Coptis chinensis rhizome and evaluated their MAO inhibitory action. Jatrorrhizine inhibited noncompetitively both MAO-A and -B from rat brain mitochondria with the IC50 values of 4 and 62 mM respectively (Fig. 11). Berberine only competitively inhibited MAO-A with an IC50 values of 126 mM (Fig. 12), but palamatine cannot showed any inhibitory action up to 200µM towards both isoenzymes. The work indicated that jatrorrhizine and berberine are the MAO inhibitors present in C. chinensis [37]. Lee et al. investigated MAO inhibition activity in mouse brain from benzophenanthridine alkaloids, such as sanguinarine and chelidonine which are the major components of the herb of Chelidonium major L. Their research revealed that sanguinarine exhibited an inhibitory effect on MAO activity in a concentration dependent manner with an IC50 value of 24.5 µM. But chelidonine did not inhibit MAO activity [38].
Fig. (9).
Fig. (11). Fig. (10).
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Kong et al. evaluated the rat brain mitochondrial monoamine oxidase MAO-A and B inhibitory action of piperidine class of alkaloid piperine and found an IC50 value 49.3 and 91.3 µM (Fig. 13) respectively. They postulated that the discerned inhibition could be presumably initiated by the hydrogen bonding of its naked amide with active protons such as –NH–, –OH and –SH in the active sites of both type of MAO [39]. Herraiz et al. introduced a new chromatographic method to measure MAO-enzymatic activity of β-carboline alkaloids by using kynuramine as a non-selective substrate with its MAO-oxidation product subsequently analysed by RP-HPLC–DAD and HPLC–mass spectrometry (MS). Their research concluded that several β-carbolines such as tryptoline (1, 2, 3, 4-tetrahydro-β-carboline) and 1-methyltryptoline (1-methyl-1, 2, 3, 4-tetrahydro-β-carboline) were inhibitors of MAO-A [40]. Han et al. isolated some quinolone alkaloids from Evodiae fructus and investigated their mouse brain mitochondrial monoamine oxidase MAO inhibitory action. They isolated six alkaloids such as, 1-methyl-2undecyl-4(1H)-quinolone, 1-methyl-2-nonyl-4(1H)-quinolone, 1-methyl-2-[(Z)-6-undecenyl]-4(1H)-quinolone, evocarpine, 1-methyl-2-[(6Z, 9Z)-6,9-pentadecadienyl]-4(1H)-quinolone, and dihydroevocarpine from unripe fruit of Evodia rutaecarpa. In this series of alkaloids, the compounds 1methyl-2-nonyl-4(1H)-quinolone (Fig. 14) and 1-methyl-2[(6Z, 9Z)-6, 9-pentadecadienyl]-4(1H)-quinolone (Fig. 15) showed significant MAO-B inhibitory action with an IC50 value of 2.3 and 3.6 µM respectively [41]. Lee et al. isolated three methylpiperate derivatives from piper longum and evaluated their inhibition of monoamine oxidase. From this series methylpiperate (Fig. 16) selective inhibitory against mouse brain mitochondrial monoamine oxidase MAO-B with an IC50 value of 1.6 µM [42].
Mathew et al.
Fig. (15).
Fig. (16).
Al-Baghdadi et al. isolated some piperine alkaloids from piper nigrum and found that potent MAO-B inhibitors. From the isolates the compound (2E)-3-(1, 3-benzodioxol-5-yl)-1(4-methylpiperidin-1-yl) prop-2-en-1-one (Fig. 17) selectively inhibit the MAO-B with an IC50 value of 0.497µM. They correlated their results with molecular docking studies and found that the lead appreciably positioned in the inhibitor binding cavity (IBC) of MAO-B [43]. Passos et al. isolated a series of indole type alkaloids from Psychotria species and investigated their MAO inhibition and molecular docking studies. Interestingly it has been found that all the indole type alkaloids showed 0.85 to 2.14 µM for human recombinant MAO-A inhibition [44].
Fig. (17).
Fig. (12). Fig. (18).
XANTHONES AS THE SOURCE FOR MAO INHIBITION Fig. (13).
Fig. (14).
Rocha et al. isolated three known xanthones such as 1, 5dihydroxyxanthone, 5-hydroxy-l-methoxyxanthone and 6-deoxyjacareubin from a dichloromethane extract of stems and roots of Hypericum brusiliense. From the isolated xanthones, 1, 5-dihydroxyxanthone (Fig. 18) showed a significant inhibition towards mouse brain mitochondrial monoamine oxidase MAO-A with an IC50 value of 0.73 µM [45]. Hwang et al. isolated from prenylated xanthones from the root bark of Cudrania tricuspidata. Among the xanthones cudratricusxanthone exhibited moderate inhibitory effects on mouse brain monoamine oxidase (MAO) with an IC50 value of 88.3µM [46]. Urbain et al. isolated some xanthones from
Plant Secondary Metabolites- Potent Inhibitors of Monoamine
Gentianella amarella ssp. acuta and investigated their monoamine oxidase inhibitory activity. Two new xanthone glycosides, corymbiferin 3-O-β-D-glucopyranoside and swertiabisxanthone-I 8ʹŒ-O-β-D-glucopyranoside were isolated from this plant, along with eight known xanthones such as triptexanthoside C, veratriloside, corymbiferin 1-O-glucoside, swertianolin, norswertianolin, swertiabisxanthone-I, bellidin, and bellidifolin. Among them bellidin and bellidifolin showed interesting inhibitory activity towards rat brain mitochondrial monoamine oxidase MAO A, while swertianolin, the 8-O-glucopyranoside form of bellidifolin, gave 93.6% inhibition of MAO B activity at 10-5 M [47]. CONCLUSION The current review made an attempt to reveal the tremendous pharmacological profile of natural plant secondary metabolites against MAO inhibition. The in vitro studies suggested that natural products showed an IC50 values ranges from micro to nano molar range against both isoforms of MAO. The in silico studies correlated in many works to explore the molecular mechanism of drug on the receptor level. This can provide the clue for the structural requirement of various class of natural metabolites for the enzyme inhibition. Apart from this many unexplored natural compounds are still there against the disorders raised by increased metabolism of biogenic amines in the central nervous system. CONFLICT OF INTEREST The authors confirm that this article content has no conflicts of interest. ACKNOWLEDGEMENTS The authors are thankful to the Library access provided by the Grace College of Pharmacy, Palakkad, India.
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Received: July 10, 2014
Revised: August 07, 2014
Accepted: August 18, 2014
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