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152
HO
H
H
Stizolamine
O
N,Ndimethylt
O
OH
HO
HO
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S. Aslam etal.
SH
HO
O
NH
O
2
Glutathione
O
N
N
N
H
N
NH
O
H
N
OH
O
HO
Serotonin
(5-Hydroxytryptamine)
O
NH
2
2
O
Flavone
Fig. 7.5 Phytochemical constituents of Mucuna prureins
H
N
ryptamine
MeO
N
5-OMe-N,Ndimethyltryptamine
H
N
N
N
O
NH
2
O
N
N
Harmine
NH
O
HN
O
Melanin
HO O
HO
HO
O
P
OH
HO
P
P
O
OH
OH
OH
OH
OH
P
O
O
P
O
O
OH
O
P
OHO
O
O
Phytic acid
OH
OH
OH
HO
O
OH
HO
O
O
HO
HO
OH
OO
O
O
OO
O
O
O
OH
O
OH
Tannin
OH
OH
OH
HO
O
OH
O
O
O
OH
OH
OH
O
O
OH
OH
O
OH
OH
O
HO
HO
HO
HO
OH
HO
OH
OH
O
OH
O
OH
O
OH
O
OO
O
OH
O
OH
OH
OO
O
O
Saponin
Fig. 7.6 Phytochemical constituents of Mucuna prureins
7.11 Medicinal Importance
Some pharmacological roles of Mucuna prureins are elaborated below (Fig.7.7).
Mucuna has therapeutic properties in all of its components [67]. The presence of
L-dopa is most likely the reason why M. pruriens extracts have been shown to
include substances with a wide variety of pharmacological effects, including
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Fig. 7.7 Medicinal activities of Mucuna prureins
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neuroprotective, anti-diabetic, anti-inammatory, and anti-oxidant properties. [68,
69]. The primary phenolic ingredient in Mucuna seeds is L-dopa (about 5% pheno-
lic substances) [70].
Mucuna is now being extensively researched since L-dopa is utilized as a rstline therapy for Parkinson’s disease (PD). Mucuna pruriens has been employed as a
carminative, hypertensive, and hypoglycemic agent. Diarrhea, cough, asthma, cancer, oedema, craziness, inammation of the membranes that surround the lungs,
cholera, ringworm, sores, snakebite, tumors, and bacterial infection (arising due to
sexual contact)are all treated with it (Fig.7.8).
The rasa, or avour, of Mucuna is mostly sweet and bitter. It has a warming virya
(body action) and a pleasant vipaka (post-digestive impact). This herb is great for
creating ojas, the body’s reservoir of necessary energy, immunity, and vigour, due to
its feeding and building capabilities.
Mucuna pruriens is an excellent source of dietary protein [71]. In African
nations, M. pruriens consumption is crucial in preventing malnutrition, for instance
Nigeria and Benin [72], as well as in Central American countries for example
Honduras [73]. In the eighteenth and nineteenth centuries, M. pruriens was also
used as a food crop in Ghana and Mozambique. In the mid-1980s [74], the ladies of
the World Neighbors’ advancement programme held in El Rosario, Honduras, used
M. pruriens as a substitute for espresso, cocoa, and wheat our, and produced 22
formulations that were simple to design, deeply nutritious, and made with locally
available materials. The programme highlighted the benets of Mucuna pruriens
construct nutria-chocolate on nursing mothers’ milk production and how their
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Clinical trial:
Suggested as better alternative
for Parkinson treatment for
future drug design prospective
S. Aslam etal.
Geographical distribution:
Largely found in India,
Bangladesh, Malaysia and
Srilanka
Chemistry:
L-dopa, Mucunadine, 1,2,3,4tetrahydroisoquinoline,
prurieninine, 6methoxyharman
Toxicology:
Toxic to human health due to
presence of L-dopa and
tryptamines
Pharmacology:
Show antioxidant,
antiparkinson, antimicrobial
and anti-inflammatory activity
Traditional uses:
Roots: Nervous disorder
Seeds: Parkinson disease
Fig. 7.8 Overall graphical representation of Mucuna prureins
breastfed children went from having second-degree malnutrition to having none at
all in just 2 months [75]. M. pruriens is traditionally boiled and pulverized in
Mexico to produce Nescafé, the most popular espresso in Central America.
7.12 Anti-oxidant Activity
Polyphenols are well known for their antioxidant activities, and are found in the
seeds, leaves and peptide fractions of Mucuna prureins. Studies have been reported
with different plant extracts.
Seed: Aqueous extract of Mucuna prureins seeds was observed, which was
found to be remarkably rich in phenol (3730.1±15.52mg) and gallic acid equivalent (GAE)/g). The phenolic contents have a direct relationship to antioxidant
effects. Gallic acid (a Standard drug) demonstrated the greatest activity at all concentrations, but the extract demonstrated greater activity at lower concentrations
(0.02, 0.01, 0.005 and 0.0025 mg/ml) and lower activity at higher concentration
0.4mg/ml when compared to another standard drug rutin [76].
Among phenolic components, appreciable amount of L.dopa is present in the
seed of M. prureins. Rima etal. recently reported the antioxidant activity of L.dopa
(isolated from dilute methanol extract) in terms of IC50, value which was found to
be 8.92±0.03ppm [77] whereas Biswas & and his coworkers previously reported
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the same work in aqueous media was with a 9.22 mcg/ml IC50 value. The whole
analysis was done by using DPPH (2,2-diphenyl-1-picrylhydrazyl) assay [78].
Dhanani etal. also worked on the seed extract of M. prureins by employing three
different methods; conventional reuxing method, ultrasound assisted solvent
extraction (UASE) method and microwave assisted solvent extraction (MASE)
method. It was reported that MASE method produced the best results in shorter
time. The IC50 value recorded in this study was 5.0μg/ml in 5 minute duration,
L.dopa and total phenolic content recorded in the same duration were 5.4±0.05 and
9.2±0.11 respectively [79].
Leaf: A study was carried out by using an aqueous leaf extract of M. prureins,
which showed antioxidant activity, ABTS (2,2′-Azino-bis(3-ethylbenzothiazoline-6-
sulfonic acid) diammonium salt) analysis indicated better antioxidant activity at
lower concentrations [80]. The phytochemicals in the leaf extract, including the
avonoids, saponins, and tannins, have antioxidant properties [81].
Peptide fraction: In a separate investigation, the in-vitro antioxidant impact of
peptide fractions obtained from M. prureins on the HeLa cell line was investigated.
It was elucidated that the peptide fractions with a molecular weight of <3 kDa
showed the highest antioxidant activity [82].
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7.13 Anti-diabetic Activity
Plants could also be the potent anti-diabetic agents. This plant has been found to be
advantageous for the treatment of diabetes in various countries such as India, Brazil,
Spain, and Germany [83]. It has been observed that M. pruriens seed alcohol extract
revealed to have a hypoglycaemic effect in normal [84], streptozotocin [83] and
alloxan [84] mice suffering from diabetes. The anti-hyperglycaemic effect was only
detected after 3 weeks at high doses, and most of the effect was noticed after
15weeks of regular intake of 200mg/kg/day, which was 47%. In alloxan-induced
diabetic rats (plasma glucose >450mg/dL), the intake of 5, 10, 20, 30, 40, 50, and
100mg/kg of M. edulis coarse extract of ethanol indicated the reduction in blood
glucose levels in 18.6, 24.9, 30.8, 41.4, 49.7, 53.1, and 55.4% by the administration
of pruriens seeds after 8hours of treatment. Whereas, 59.7% reduction resulted by
the ingestion of glibenclamide (5mg/kg/day) [85].
Similar research has been conducted by injecting streptozotocin (65mg/kg body
weight) into normal healthy rats. Four groups were made; Group A (normal rats),
Group B (diabetic control), Group C (Mucuna prureins; experimental drug, 200mg/
kg), Group D (glibenclamide; standard drug, 1 mg/kg body weight). Mucuna
Prureins extract was found to be effective in showing hypoglycemic activity when
compared to the diabetic control group. Weight loss is a common symptom in diabetics, but when administered with M. prureins and Glibenclamide drugs, weight
gain was observed, more in the case of M. prureins than Glibenclamide [86]. In
similar study as above, it was revealed that M. prureins alleviated blood glucose
levels from 242.4±9.2mg/dl to 91.0±5.2mg/dl, hence making it a green tool to
be consumed as therapy in hyperglycemic conditions [87].
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S. Aslam etal.
7.14 Anti-depressant Activity
Depression is a life-threatening disease; this psychiatric condition affects 20% of
the world’s population [88]. Mucuna prureins seeds have antidepressant properties.
Hydroalcoholic extract of M. prureins seeds was investigated for serotonin and noradrenaline mediated antidepressant action. Results revealed that the seed extract
interacted with serotonergic and noradrenergic systems to show antidepressant
behavior [89]. To clarify the antidepressant properties of Mucuna pruriens seeds, a
similar investigation was carried out using the hydroalcoholic extract of the seeds
and dealt with the dopaminergic modulating action. Results explored that there was
a reduction in stress levels, which were investigated by using Forced swimming test
(FST) and Tail suspension test (TST) [90].
7.15 Anti-inammatory Activity
Mucuna prureins also played its role in reducing inammation as it is linked to the
pathophysiology of various diseases like arthritis, cancer, and gout. Mucuna pru-
reins essential oil (MPEO) obtained from the leaf of a plant expressed an antiiammatory response. A study was carried out with ve different groups to assess
MPEO anti-inammatory activity via a formalin induced assay. Group I: Control
(Saline solution), Group II: Standard (peroxicam), Group III: MPEO (100mg/kg),
Group IV: MPEO (200mg/kg), Group V: MPEO (400mg/kg). The standard drug
peroxicam 10mg/kg showed 100% inhibition with 16.5 ±2.8 licks, while groups IV
and V showed 100% inhibition with different numbers of licks (57.2± 5.1) and 33.3
± 7.1, respectively [91]. A similar study has been conducted to see the antiinammatory action of Mucuna prureins seed in ve groups of mice. Group I (control; tragacanth solution), Group II (standard; Aspirin, 100mg/kg), Group III, IV, V
contained 1,2 and 3g/kg of M. prureins seed respectively. Inammation was induced
by carageenan which is attributed to the release of histamine. It was observed that
by increasing the dose of M. prureins seed, there was a subsequent increment in its
anti-inammatory response [92].
M. prureins nanoparticles (NPs) were synthesized and analyzed for their antiinammatory action. Copper nanoparticles and titanium dioxide nanoparticles have
been synthesized, characterized and recently reported for their anti-inammatory
activity. TiO2 nanoparticles at 50μL concentration exhibited 90% inhibition [93]
while with Cu-nanoparticles the percentage inhibition was 71% at 50μL [94].
7.16 Antimicrobial Activity
M. prureins seed extract functionalized with zinc oxide nanoparticles (NPs) showed
an antibacterial response against Bacillus subtilis. The activity was assessed with
growth kinetics evaluation and broth dilution assay. The ZnO nanoparticles
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indicated MIC value of 20μg/ml and IC50 value of 70μg/ml. Inorganic metals are
well known for their antibacterial effects. Nanoparticles using M. prureins extract
act as biocidal agent in a cheap and nontoxic manner [95].
The phytochemicals, phenols, and tannins in M. prureins leaves demonstrated
antibacterial activity in a crude methanolic extract. Activity was evaluated against
E.coli, Bacillus subtilis, Salmonella typhi and Shigella disenteriae. A higher value
of the zone of inhibition for E.coli (2.8cm) shows higher antimicrobial potency
than B.subtilis (2.1cm) [96]. After that another study was made to see the antimicrobial action of M. prureins seed using disc fusion method, for which alcoholic
extract was used. Zone of inhibition values for different microbes were observed;
Vibrio cholera (9.4mm inhibition zone), Vibrio harveyi (16.8mm inhibition zone),
S. aureus (3.4mm inhibition zone) and E. coli (4.1mm inhibition zone) [97].
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7.17 Antivenom Activity
The seeds of M. pruriens are often used in traditional medicine to prevent the negative consequences of a snake bite brought on by cytotoxins, neurotoxins, the PLA2
enzyme, cardiotoxins, and proteases. It has been demonstrated that M. pruriens is
more effective than snake poison. Traditional practitioners in Plateau State, Nigeria,
recommend the seed as an oral medicine for snake bite, claiming that the ingestion
of seeds resulted in the person’s being protected from the symptoms of any snake
bite for the whole year [98].
A study was investigated on the anti-venomous function of M. prureins leaf
extract against cobra snake venom by dividing mice into six different groups; Group
A (normal control), Group B (test control; snake venom was induced i.e., 0.075mg/
kg), Group C (standard control; antivenin) and Groups D, E & F were given ethanolic extract of M. prureins in 40mg/kg, 60mg/kg, 80mg/kg respectively. The extract
at 80mg/kg was found to be more effective than the standard drug antivenin [99].
In vitro analysis was done to see anti-venial potential of M. prureins seeds against
various snake venoms. Experiments were carried out on rats which were pretreated
with M. prureins seed extract and then injected with venom. Anti-MPE antibodies
prevented fatalities caused by various venoms [100].
7.18 Nociceptic Activity
Pain is a very unpleasant event. M. prureins seeds are widely used as analgesics for
mellenia. The investigation was done in four separate groups: Group A: (Control),
Group B: (Standard; Aspirin), Group C: (avonoids), Group D: (alkaloids) via formalin paw licking test. It was observed that avonoids (mean number of lickings:
24.25 ± 8.97) showed signicantly more analgesic activity than alkaloids (mean
number of lickings: 39±6.78) [101].
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In-vivo analysis of the nociceptic activity of Mucuna prurein was done by using
Eddy’s hot plate method. Four groups were categorized to carry out to the reaction;
Group A; (standard; tramadol, 25mg/kg), Group B, C, D of 100mg/kg, 200mg/kg
and 400mg/kg were used as trials. By using oral feeding, analgesic activity was
noted at different time intervals, such as 0, 30, 60, 90, 120 and 150minutes. The
results obtained were most effective at 400mg/kgM. pruriens extract [102].
S. Aslam etal.
7.19 Anti-obesity
Obesity is becoming a global epidemy [103] which causes many pathophysiological
complications such as diabetes [104], cardiovascular diseases [105], immunological
changes [106], psychiatric changes [107] etc. A recent study revealed that the milk
of Mucuna prureins seeds has the ability to inuence weight gain and blood lipid
levels. The two varieties of Mucuna prureins seeds (var. Cochinchinensis and var.
Veracruz mottle) were studied. For this purpose, 7 groups of healthy male Wistar
rats were made for the hyperlipidaemic study. Group I; (Fed with normal diet; control group), Group II; (Fed with high fat; Hyperlipidaemic control group), Group
III; (Fed with high fat with standard drug; Atorvastatin) Group IV; (Fed with high
fat +20ml dehulled Cochinchinensis milk/ day), Group V; (Fed with high fat +20ml
of whole Cochinchinensis milk/ day), Group VI; (Fed with high fat +20ml dehulled
Veracruz milk/ day), Group VII; (Fed with high fat +20ml whole Veracruz milk/
day). The results found were astonishing in terms of triglycerides, total cholesterol
levels, low density lipoprotein cholesterol, high density lipoprotein cholesterol and
very low-density lipoprotein cholesterol. All the test groups had the most effective
outcomes in comparison to the standard drug, Atorvastatin [108].
Similar study was held to check Mucuna prureins’ anti-obesity functions on
obese and healthy rats. Four groups were made to observe changes by administering
Mucuna prureins extract. Group I; (Healthy group; HG), Group II; (Healthy group
administered with Mucuna prureins extract; HGMP) Group III; (Obese group; OG);
Group IV; (Obese group administered with Mucuna prureins extract; OGMP).
Mucuna prureins were found to lower the cholesterol levels in all groups that were
given Mucuna prureins extract as an antihyperlipidemic [109].
7.20 Aphrodisiac Activity
Sexual dysfunction is a problem that can be treated through medications and surgeries. Herbal remedies, on the other hand, were thought to be a solution to improve
sexual life [110]. For this, Mucuna prureins plant seeds were used for therapeutic
purposes in Tibb-e-Unani [111]. Mucuna helps to promote fertility, healthy sperm
and ova, correct reproductive organ functions, and healthy vaginal secretions.
Aphrodisiac Mucuna pruriens encourages healthy sexual energy and desire.
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To determine the impact of including Mucuna prureins seeds in the diet, a study
on rabbits was conducted. Mucuna prureins seed meal (MSM) was administered in
different concentrations for 3 months trial. Results collected indicated positive
effects on rabbits’ sexual behavior, reproductive organ weight, and semen characteristics [112]. Diabetes patients frequently experience sexual dysfunction. Suresh
etal. studied the efcacy of M. prureins on sexual behaviors in induced diabetic
male rats. Diabetes was induced by using streptozotocin. Groups were classied
into 6 categories; Group I (control group), Group II (diabetic rats; diabetes was
induced by streptozotocin), Group III (diabetic rats were given 200mg/kg b.w. of
M. prureins extract), Group IV (diabetic rats were given 5mg/kg b.w. of sildenal
citrate), and Group V (normal rats were given Mucuna prureins extract). The results
showed that group II had considerably lower levels of daily sperm production
(DSP), luteinizing hormone, and testosterone, but group III had improved sexual
behavior, sperm parameters, DSP, and hormonal levels compared to group II [113].
159
7.21 Anti-Parkinson’s Activity
Various clinical trials were conducted in Parkinsons’ disease patients, and the results
showed that M. pruriens seeds are useful for the diagnosis of Parkinson’s disease
[114, 115]. The bioavailability experiments were conducted with the HP-200
Mucuna seed formulation, and it was revealed that the pharmacokinetic prole was
comparable to that of L-dopa [116]. It was reported in previous studies that Mucuna
seed powder had a quick beginning of action and lasted longer without causing
dyskinesias, suggesting that Mucuna contains elements that boost L-dopa activity
(Fig.7.9).
L-Dopa correlates to the derivatives of methylated and non-methylated tetrahydroisoquinoline in modest concentrations (about 0.25%) [117, 118]. Mucuna seeds,
leaves, stem, and roots contain these compounds. N,N-dimethyl tryptamine and certain indole compounds are among the other chemical constituents found in various
regions of the plant [119
oxidant and anti-oxidant compounds that affect oxidative DNA damage and may
protect tissues from damage caused by neurodegenerative illnesses such as parkinsonism [120].
Mucuna prureins seed extract was thought to contain 12.55% L.dopa content,
used to treat Parkinson’s disease [121], in addition to other phytochemicals [122].
The medicinal interventions of M. prureins have been discussed in a number of
studies.
L.dopa pharmacokinetics was observed in three different M. prureins samples:
roasted, dried and boiled. Roasted M. Prureins seeds contain 5.3% and dried
M. Prureins seeds contain 5.29% L.Dopa while boiling reduced M. Prureins’
L.dopa content up to 70%. M. prureins’ L-dopa dose will be effective if administered at a dose greater than 3.5X that of standard levodopa+dopa decarboxylase
inhibitor [123]. Ethanolic extract of M. prureins seed was assessed in a
].L-dopa and its metabolites were discovered to be pro-
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Block action of Ach
HO
COOH COOH
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S. Aslam etal.
Brain
Substantia Nigra
Amantadine
Stimulate uptake of DA
Inhibits reuptake
DA Agonist
Bind to DA receptor
HO
Release
L-tryosine
NH
2
DA receptor
HO
L-dopa
HO
HO
Dopamine
Reuptake
NH
2
COOH
NH
2
MAO-B
DADA
COMT
Acetylcholine inhibitor
Increase the level
of Levodopa
Selegline
Inhibits MAO-B
Degradation
COMT inhibitor
Block degradation of
L-dopa
And dopamine
Fig. 7.9 Metabolic pathway of L-dopa agent against Parkinson disease
1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Standard was estrogen, a well- known therapeutic agent for Parkinson’s disease. The whole experiment
was conducted on mice which were divided into four different groups; Control,
MPTP, MPTP & M. prureins, MPTP & estrogen. It was revealed that MPTP +
M. prureins group was found to be more effective than MPTP + estrogen group in
recovering all of the deciencies induced by MPTP including dopaminergic neuron
reduction resulting in low dopamine level and accumulation of abnormal protein
synuclein resulting in lewy body formation [124].
7.22 Synthesis ofL-Dopa
Due to the catalytic amount of osmium tetraoxide and chiral ligands such as
hydroquinine- 1,4-phthalazinediyl diether [(DHQ)2-PHAL], beta-methyl styrene
and,-unsaturated ester (1) were subjected to an AD reaction to produce chiral diol
(2) in perfect enantiomeric excess. The cyclic sulte was obtained as an intermediate by treating vicinal diol (2) with SOCl2 in the presence of NEt2 in CH2Cl2 at zero
degrees celcius. When the cyclic sulte intermediate was reacted with sodium azide
in a solvent (DMF) at 80°C, high yields of the derivative azido alcohol (3) were
produced [125, 126]. The enantiomeric excess of azido alcohol (3) was identied
using 1H and 19F NMR of its Mosher ester, and the compound (3) was then
lux,
92%; (e)6MHCl,phenol, acetic acid,130-135°C,24h,70% yield, 85%ee.
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161
(3)
N
3
Et
CO
2
OH
Et
O
CO
2
(a)(b)
O
(1)(2)
OH
Et
OH
CO
2
O
O
O
O
(c)
H
Et
NH
CO
2
2
O
O
L-Dopa
Reagents andConditions;
(a)cat.OsO
NaN
,
acetone-H
3
,
-PHAL, K
4
2
(DHQ)
O, 80°C,82% yield, 95%ee; (c)PPh
2
(e)
Fe(CN)
3
Et
NH
CO
2
(d)
2
O
O
O
O
(5)
,
,
K
CO
t-BuOH-H
2
6
3
O, 0°C, 85%; (b)SOCl
2
,
CH
CN,90%;(d) 10%Pd/C, HCO
3
3
,
NEt
2
N
Et
CO
2
OH
(4)
,
,
0°C, 88%;
CH
Cl
2
2
3
,
MeOH,ref
NH
4
2
Scheme 7.1 Synthesis of L-dopa
subsequently reacted with PPh3 in CH3CN to produce chiral aziridines (4) in high
yield. When aziridine (4) was exposed to Pd-catalyzed reductive ring opening using
NH4HCO2 (ammonium formate) as a source of hydrogen, at the benzylic position,
it underwent the stereospecic and regioselective ring opening, yielding amines (5).
Finally, after reacting with 6 molar of HCl in phenol and acetic acid at 130–135°C,
aminoester (5) yielded 85% L-dopa (Scheme 7.1) [127].
7.23 Metabolic Pathway ofL-dopa
L-Dopa is a catecholamine that is formed when tyrosine is hydroxylated, and it is a
precursor to neurotransmitters including adrenaline, noradrenaline, and dopamine. In
particular, L-dopa is considered as a signicant precursor in the production of melanin,
which is present in a number of tissues in both plants and mammals. The Cu-consisting
enzyme tyrosine hydroxylase used to hydroxylate the residues of tyrosine, in the existence of molecular O
, resulting in the production of L-Dopa. Plants have an L-Dopa
2
production pathway that is similar to that of mammals. Tyrosine hydroxylase is a
Cu-containing enzyme that hydroxylates tyrosine residues in the presence of molecular O2, resulting in the production of L-Dopa (Scheme 7.2) [128–130].
7.24 Future Perspectives ofPlant
Mucuna beans have been shown to be effective in the treatment of ageing, rheumatoid arthritis, diabetes, infertility in men, and neurological disorders. As a result,
more study is needed to understand the specic mechanism by which Mucuna beans
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