130

H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

J. Med. Chem. Sci. 2 (2019) 130-139

Journal Homepage: http://jmchemsci.com

A Review on Classes, Extraction, Purification and Pharmaceutical Importance of

Plants Alkaloid
Hamzat T. Adejokea, Hitler Louisb,c*, Oluwatobi O. Amusana, Gloria Apebendeb
a
Department of Chemistry, University of Ilorin, Ilorin, Kwara State, Nigeria
b
Department of Pure and Applied Chemistry, Faculty of Physical Sciences, University of Calabar, Calabar, Cross River State, Nigeria
c
CAS Key Laboratory for Nanosystem and Hierarchical Fabrication, CAS Centre for Excellence in Nanoscience, National Centre for Nanoscience and
Technology, University of Chinese Academy of Sciences, Beijing, China.

ARTICLE INFO ABSTRACT

Article history: The importance of natural products in the pharmaceuticalindustrycannot be abated because it
Received: 27 August 2018 playsvital role in the prevention and treatments of diseasessuch as cancer, malaria, pile etc.
Revised: 13 January 2019 These natural products which include alkaloid, flavonoid, phenol, saponin and tannin are
Accepted: 8 March 2019 bioactive compounds in plant and essential in plant metabolic activities. All of these have been
tested for their huge medicinal properties and therefore could serve as an alternative medicine
Keywords: in treatment of myriad ailments. Although, through the modern-day technologies, these
Plants bioactive compounds have been separated from the plants and synthesized into capsules and
Alkaloids tablets for easy administration, usage and storage, there is a need to create awareness on the
structure side-effects associated with excess or abuse of medicinal plants and to encourage rational use
pharmacology of natural resources for sustainability. Thus, this review gives an overview on pharmacological
importance of named alkaloids, methods of extraction and purification of alkaloids in plant,
laying emphasis on side-effects associated to the abuse of alkaloids or alkaloid derivative
drugs.

GRAPHICAL ABSTRACT

1. Introduction the prevention and treatment of cancer and other disease

around the world.Many systems of medicine like Ayurveda

A lkaloids are group of naturally occurring chemical

compounds that mostly contain basic nitrogen atoms
produced by a large variety of organisms
and Chinese medicine utilize natural products as the source of
drugs for 100 decades.1 The secondary metabolites from the
natural products serve as a foundation for the development of
including bacteria, fungi, plants, and animals. It is one of the a large number of drugs. As compared to most other classes of
diverse groups of secondary metabolites which play an natural compounds, alkaloids are characterized by a great
important role in the ecology of organisms and synthesize structural diversity as there is no uniform classification of
them by acting as a defense system against pathogens and alkaloids. First, classification methods historically combined
animals. The applications of alkaloids are not restricted to alkaloids by the common natural source, e. g., a certain type
biological control of herbivores but they also have of plants. This classification was justified by the lack of
pharmacological, veterinary and medical importance. They knowledge about the chemical structure of alkaloids and is
are natural products and have been playing a critical role in now considered obsolete.

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* Corresponding Author:
http://jmchemsci.com
E-mail address: Louis@nanoctr.cn (H. Louis)
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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

Alkaloids exhibit a broad range of very specific or rectally.9 As stated above, morphine was first isolated
pharmacological characteristics which can be used as a strong between 1803 and 1805 by Friedrich Sertürner. This is
basis for the general classification of the wide spectrum of generally believed to be the first isolation of an active
alkaloids derived from the plant kingdom, such as analgesic, ingredientfrom poppy straw of the opium poppy. In 2013,
central nervous system stimulants and depressants, anti- approximately 523 tons of morphine was produced and
malarial, cardio-vascular drugs and the like. The role of approximately 45 tons were directly used for pain. About 70
alkaloids for the living organisms that produce them is still percent of morphine is used to make other opioids such
unclear. It was initially assumed that the alkaloids are the as hydromorphone, oxymorphoneand heroin. Morphine has
final products of nitrogenmetabolism in plants, as urea in also been used traditionally in the treatment of acute
mammals. It was later shown that alkaloid concentration pulmonary edema, although there is little evidence to support
varies over time, and this hypothesis was refuted. Most of the this practice.10 Morphine is beneficial in reducing the
known functions of alkaloids are related to protection e.g. symptom of shortness of breath due to both cancer and non-
morphine is a popular analgesic. In addition, the presence of cancer causes.11, 12 Low dosage sustained-release of morphine
alkaloids in the plant prevents insects and chordate animals significantly reduces breathlessness and minimal exertion
from eating it. However, some animals are adapted to from conditions such as advanced cancer or end-stage
alkaloids and even use them in their own metabolism. Such cardiorespiratory diseases.13
alkaloid-related substances as serotonin, dopamine and
histamine are important neurotransmitters in animals. The Side effects of morphine
superior potential of alkaloid-containing plants and their
contained alkaloids which continue to contribute to the health Adverse effects of morphine include constipation by reducing
and welfare of future generations in a sustainable manner gut motility. Clinical studies consistently conclude that
have been demonstrated in several articles alongside their morphine, like other opioids, often causes hypogonadism; a
potential side-effects.2 condition that causes poor functioning of testes in men and
ovaries in women and also responsible for hormone
Pharmaceutical importance of alkaloids imbalances in chronic users of both sexes. This side effect
morphine is dose-dependent and occurs in both therapeutic
The first alkaloids for medicinal use were isolated at the and recreational users. Morphine can interfere with
beginning of 19th century, by Derosne (opium salt, narcotine) menstruation in women by suppressing levels of luteinizing
and Sertürner (principium somniferum, morphine). The hormone. Many studies suggest that the majority (perhaps as
chemical identification of morphine was carried in 1923, by much as 90%) of chronic opioid users have opioid-induced
Robinson and Gulland. So far, there are more than 20000 hypogonadism. This effect may cause the increased likelihood
identified alkaloids and a number of them have played an of osteoporosis and bone fracture observed in chronic
important role in clinical practice.3 They present numerous morphine users. Studies suggest that the effect is temporary.
biological activities such as being emetic, anticholinergic, As of 2013, the effect of low-dose or acute use of morphine
antitumor, diuretic, sympathomimetic, antiviral, on the endocrine system is unclear.14 In terms
antihypertensive, analgesic, antidepressant, muscle relaxant, of cognitive abilities, morphine may have a negative impact
anti-inflammatory, antimicrobial, and antiulcer. The alkaloids on anterograde and retrograde memory15, but these effects are
have proton-accepting nitrogen atom and one or more proton- minimal and transient.
donating amine hydrogen atoms, which form hydrogen bonds Overall, acute doses of opioids in non-tolerant users
with proteins, enzymes, and receptors. Furthermore, they, produce minor effects in some sensory and motor abilities,
generally, have functional groups such as phenolic hydroxyl and also in attention and cognition. It is likely that the effects
which might be responsible for the exceptional bioactivity of of morphine will be more pronounced in opioid-naive subjects
the alkaloids.4 Antioxidant activities of alkaloids have also than chronic opioid users. One of the big risks of morphine
been presented in different experimental models and use is that addiction to the drug develops quickly. An
pathological conditions.5–7 Quinine and other cinchona addiction to the drug means that the user requires more and
alkaloids including quinidine, cinchonine and cinchonidine more of it to feel the same effects formerly felt from a smaller
are effective against malaria;alkaloids belonging to beta- dose. As higher and higher doses are regularly taken, the
carboline group possess antimicrobial, anti-HIV and chances of a deadly overdose increase. Furthermore,
antiparasitic activities.8 Morphine is used in suppressingthe morphine activates the brain’s “pleasure centers,” which
feeling of pain and boldine alkaloids have antioxidant means that taking the drug is usually considered highly
activities. enjoyable by the addict, causing him or her to focus all
energies and efforts on securing more morphine.
Pharmaceutical Importance of Named Alkaloids

Morphine

Morphine is a pain medication which is found naturally in a

number of plants and animals. It acts directly on the central
nervous system(CNS) to decrease the feeling of pain. It can
be taken for both acute pain and chronic pain either by mouth,
being injected into a muscle or under the
skin, intravenously, into the space around the spinal cord,

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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

Fig. 1. structures of morphine comparable results in HIV-negative patients.20 In a

subsequent study in the same region, no significant
differences in treatment response were observed between
Biosynthesis of morphine children with progressive HIV infection and HIV-uninfected
controls treated with oral quinine.
Morphine is an endogenous opioid in humans that can be
synthesized by and released from various human cells,
including white blood cells. The morphine biosynthetic
pathway in humans occur as follows:L-tyrosine → para-
tyramine or L-DOPA → dopamine → (S)-norlaudanosoline
→ (S)-reticuline → 1, 2- dehydroretinulinium →(R) reticuline
→ salutaridine → salutaridinol → thebaine → neopinone → c
odeinone→ codeine → morphine.16 It is also biosynthesized
in the opium poppy from the tetrahydroisoquinoline reticuline
. It is converted into salutaridine, thebaine, and oripavine. The
enzymes which are involved in this process are
the salutaridine synthase, salutaridine: NADPH 7-
Fig. 2. structures of quinine
oxidoreductase and the codeinone reductase.17

Quinine Quinine resistance

Malaria is one of the most widespread infectious diseases in Over the years, malaria parasites have developed resistance to
the world. Nearly 1 million deaths of mostly children were a number of commonly used anti-malarial drugs. However,
caused by malaria. Currently, there are over 100 countries the development of resistance to quinine has been slow with
battling with malaria, of which 45 of these countries are the drug retaining some activity but having its action delayed
within African region. In spite of the fact that malaria is or diminished. Diminished sensitivity of P. falciparum to
curable and preventable, its prevalence increased in the 1980s quinine has been widely documented in Asia and South
and 1990s as the malaria parasites developed resistance to the America 21 but it seems relatively uncommon in Africa where
commonly used malaria drugs. Migration, low standard of conflicting results of no resistance22, 23 or varying degrees of
living, poor health care and insufficient human and technical resistance 24 have been reported.
resources limit the effectiveness of various intervention
programs designed to control the disease. The principal goal Side effectof quinine
of WHO, UNICEF, UNDP and the World Bank was to reduce
the rate of malaria’s related mortality.18 As previously Quinine has a low therapeutic index, and adverse effects with
mentioned, quinine and other cinchona alkaloids including its use are substantial.25 The side effects commonly seen at
quinidine, cinchonine and cinchonidine are effective against therapeutic concentrations are referred to as cinchonism, with
malaria. The potency of these four cinchona alkaloids was mild forms including tinnitus, slight impairment of hearing,
evaluated in a clinical trial conducted from 1866 to 1868 in headache and nausea. Impairment of hearing is usually
over 3000 patients using sulfate salt of the alkaloids to depend on concentration and it is reversible.26 More severe
measure the cessation of febrile paroxysm. All four alkaloids manifestations include vertigo, vomiting, abdominal pain,
were found to be effective with cure rate greater than 95%. diarrhea, marked auditory loss, and visual symptoms,
However, quinine became the majorly used cinchona alkaloid including loss of vision. Hypotension may occur if the drug is
for the treatment of malaria in 1980 due to dominance of given too rapidly, and venous thrombosis may occur
South American cinchona bark which contains higher following intravenous injections. Intramuscular
proportion of quinine. administration is painful and may cause sterile abscesses.
Quinine has a swift action against intra-erythrocytic Hypoglycaemia is yet another common side effect of quinine
malaria parasites. It is rapidly absorbed both orally and therapy 27, 28 and is a particular problem in pregnant women.29
intravenously, reaching peak concentration within few hours. Hypoglycaemia has been reported to occur in up to 32% of
The combination of quinine and clindamycin has proven patients receiving quinine therapy. However in more recent
highly efficacious against multidrug-resistant strains of studies, hypoglycaemia occurred in only 3% of adults and
Plasmodium falciparum, with 42 day cure rates of 100% in 2.8% of African children receiving quinine.30 Less frequent
one study.19 The only concern with this combination is that it but more serious side effects of quinine therapy include skin
is usually not affordable for most people. During the second eruptions, asthma, thrombocytopenia, hepatic injury and
and third trimester of pregnancy, quinine monotherapy seems psychosis.
to have unacceptably low efficacy in areas with multidrug
resistant malaria when compared to ACT and therefore not Biosynthesis of quinine
effective in treatment of malaria for a pregnant woman. The
Interactions between HIV and malaria remain a major public Cinchona trees remain the only economically practical source
health concern in areas affected by both diseases. Very few of quinine. However, under wartime pressure, research
studies have evaluated the role of quinine in the management towards its synthetic production was undertaken. A formal
of malaria in HIV infected populations. The earliest study was chemical synthesis was accomplished in 1944 by American
done in the Congo in 1986 and it showed malaria cure rates of chemists R.B. Woodward and W.E. Doering. Since then,
92% in HIV infected patients treated with oral quinine with several more efficient quinine total syntheses have been
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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

achieved31, but none of them can compete in economic terms

with isolation of the alkaloid from natural sources. The first
synthetic organic dye, mauveine, was discovered by William
Henry Perkin in 1856 while he was attempting to synthesize
quinine.

Boldine

The possibilities of preventing or retarding the deleterious

effects associated with excessive production of reactive
oxygen species (ROS) with the use of previously unexplored Fig.3. structure of Boldin
groups of natural products is now an attractive subject of
research. Natural antioxidants have enjoyed an increasing Side effect of boldine
recognition and popularity during the last decade owing to
various side effects associated with the use of synthetic The precedent of the prolonged pharmaceutical use of boldine
antioxidant. Moreover, the industrial use of natural and boldine-containing drug preparations suggests that
antioxidants remained limited due to their often higher cost as boldine exhibits low toxicity. In fact, it requiresa relatively
they exist in limited quantity in their natural source and their high dosage to induce side effects, toxicity or lethality in
relatively lower activity. Boldine and other related alkaloids several mammalian species. Early studies by Kreitmair
have been shown to behave as potent antioxidants in anumber reported that 500 and 1000 mg/kg were required to induce the
of experimental models. Various studies conducted by death of mice and guinea pigs, respectively. Considerably,
revealed that boldine is particularly efficient in food lower doses of 250 and 50 mg/kg were required to induce the
preservation. It was found to protect fish oil against death of mice and guinea pigs, respectively, whereas 25
spontaneous short and long-term oxygen dependent thermal mg/kg were required to induce the death of cats.35 Most
peroxidation. Boldine displays antioxidant activity similar to animals employed in the above studies were reported to die by
that of quercetin and it has two to three time’sgreater activity respiratory failure. Studies conducted by Moreno et al.
than tocopherol, butylated hydroxyl lanisole(BHA) or reported that boldine has no mutagenicity in several Ames
butylated hydroxyl toluene(BHT). tester strains, with or without prior metabolic activation.
Pharmacological activities,such as cyto-protective, anti- Subsequently, Tavares and Takahashi reported that boldine
tumour promoting, anti-inflammatory, antipyretic and did not induce a statistically significant increase in the
antiplatelet have beenassociated with the ability of boldine to frequency of chromosome aberrations or sister chromatid
scavenge highlyreactive free radicals.Boldine exchanges in vitro in human peripheral blood lymphocytes
has antioxidant activity that effectively protects against free (up to 40 g/mL) or in vivo. Regarding the toxicity of boldine
radical induced lipid peroxidation or enzyme inactivation. In in pregnancy, Almeida et al.36 observed that its acute
addition to cytoprotective activity, it also has alpha-adrenergic administration to rats during their early pregnancy phase
antagonist activities in vascular tissue, and has also been induced no foetus abortion and no foetal malformation when
reported to have hepato-protective effects.Herbal teas given per os (orally)at 500 mg/kg. A weak but significant
containing boldine are widely consumed in South America abortive and teratogenic effect was evident at 800 mg/kg.
and boldo leaves are being continually exported to some Studying the effects of long-term administration, the same
European countries for further pharmaceutical processing to authors observed a low degree of hepatotoxicity, assessed by
boldine containing concentrates which are later used as blood transaminases or urea levels, in rats given boldine daily
additive in food and pharmaceutical industries.The photo- at 800 mg/kg for 30 and 60 days but not seen at 500 mg/kg.
protection activity was evidenced through the prevention of No hepatic histological modifications were observed at a dose
the UV induced-increase in skin temperature of the rodents. of 800 mg/kg administered for 90 days.37
More recently, Rancan et al.32-34 investigated the photo-
filtering properties of boldine in humans; he observed that the
Pilocarpine
application of boldine (25 mm) onto a 12 cm2area of the back
of volunteers protected their skin against erythema formation
Pilocarpineis a naturally occurring alkaloid derived from the
to an extent slightly lower than that of a commercial sun
leaves of South American plants of the genus Pilocarpusand
cream for which a UV-protection factor of 5 was informed. In
commercial production is derived entirely from the leaves
the same study, it was observed that the in vitro irradiation of
of Pilocarpus microphyllus.38 It stimulates the secretion of
human T lymphocytes through a thin boldine-containing
large amounts of saliva and sweat39 and it is used to treat dry
solution protected these cells against loss of viability with a
mouth (xerostomia), particularly in Sjögren's syndrome, but
potency even greater than that shown by
also as a side-effect of radiation therapy for head and neck
octylmethoxycinnamate, a UV-Breference filter.
cancer. It has also been used in the treatment of chronic open-
angle glaucoma and acute angle-closure glaucoma for over
100 years.40 It acts on a subtype of muscarinic receptor found
on the iris sphincter muscle, causing the muscle to contract
resulting in pupil constriction (miosis). Pilocarpine also acts
on the ciliary muscleand causes it to contract. When the
ciliary muscle contracts, it opens the trabecular
meshwork through increased tension on the scleral spur. This
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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

action facilitates the rate that aqueous humor leaves the eye to the brain which can lead to chronic epilepsy. Epilepsy
decrease intraocular pressure. In ophthalmology, pilocarpine induced by injected pilocarpine has been used to develop
is also used to reduce the possibility of glare at night from animal models in rodents in order to study human epilepsy.
lights when the patient has undergone implantation of phakic
intraocular lenses; the use of pilocarpine would reduce the Caffeine
size of the pupils, relieving these symptoms.
The most common concentration for this use is pilocarpine Around sixty plant species are known to contain
1%, the weakest concentration. Pilocarpine is shown to be just caffeine. Common sources are the "beans" (seeds) of the two
as effective as apraclonidine in preventing intraocular cultivated coffee plants, Coffea arabica and Coffea
pressure spikes after laser trabeculoplasty.41 It is used to canephora (the quantity varies, but 1.3% is a typical value); in
stimulate sweat glands in a sweat test to measure the leaves of the tea plant; and in kola nuts. Other sources
the concentration of chloride and sodium that is excreted in include yaupon holly leaves, South American holly yerba
sweat. It is used to diagnose cystic fibrosis. mate leaves, seeds from Amazonian maple guarana berries,
Pilocarpine is available in both tablet and capsule and Amazonian holly guayusa leaves. Temperate climates
formulation as well as a liquid-based preparation. The latter, around the world have produced unrelated caffeine-containing
however, has inherent instability and degradation problems .42 plants. Caffeine in plants acts as a natural pesticide: it can
The drug exerts a broad spectrum of pharmacological effects paralyze and kill predator insects feeding on the plant. High
with predominant muscarinic action. It can increase secretion caffeine levels are found in coffee seedlings when they are
by the exocrine glands, including the sweat, salivary, lacrimal, developing foliage and lack mechanical protection.Caffeine is
gastric, pancreatic and intestinal glands, and the mucous cells the most widely consumed psychoactive drug in the world47
of the respiratory tract. In addition, pilocarpine also increases and one of the most comprehensively studied ingredients in
smooth muscle tone and motility in the intestinal the food supply. It occurs naturally in the leaves and seeds of
and urinary tracts, gallbladder, biliary ducts, and bronchi.43, 44 many plants and has a taste bitter enough to deter pests.48 It is
a constituent of many over-the-counter pain relievers and
prescription drugs because the vasoconstriction and anti-
inflammatory effects of the alkaloid act as a compliment to
analgesics, in some cases increasing the effectiveness of pain
relievers by up to 40%.49–53
Caffeine is used for general pain relief in medications such
as Midol and Vanquis, which contains doses ranging from 33
to 60 mg. It is used therapeutically in combination with
ergotamine to treat migraine headaches and in combination
with non-steroidal anti-inflammatory analgesics. Anacin™,
Excedrin, Goody’s headache powder, and pain reliever plus
Fig. 4. structures of pilocarpine contain between 32 and 65 mg of caffeine, and prescription
headache medications, including Fiorinal, Orphenadrine, and
Biosynthesis of pilocarpine Synalgos, contain between 30 and 60 mg of caffeine. Besides,
it is used as a somnolytic to counteract drowsiness (e. g.,
Pilocarpine is found exclusively in species of Pilocarpus and NoDoze and Vivarin each contain 200 mg of caffeine), to
the presence of other imidazole alkaloids has been reported in enhance seizure duration in electroconvulsive therapy, and to
several species of the genus. Pilocarpine has several important treat respiratory depression in neonates, postprandial
pharmaceutical applications. Although several imidazole hypotension, and obesity.55–57 Similar synergistic additive
alkaloids related to pilocarpine have been reported in the effects of caffeine and medications also occur in treatments
previous years, little is still known about its biosynthetic for asthma and gall bladder diseases, attention deficit-
route. At most, histidine has been reported as the precursor of hyperactivity disorder, shortness-of-breath in newborns, low
pilocarpine. blood pressure, and weight loss.58–62 Caffeine works by
binding to adenosine receptors located in the central and
Side effect of pilocarpine peripheral nervous systems as well as in various organs, such
as the heart, and blood vessels.It can have both positive and
negative health effects. It can treat and prevent the premature
Mild and tolerable adverse reactions are frequently reported
infant breathing disorders bronchopulmonary dysplasia of
during pilocarpine therapy, their incidence being dose-related
prematurity and apnea of prematurity.
.45, 46 Most of the adverse effect of pilocarpine is related to
its non-selective action as a muscarinic receptor agonist.
Pilocarpine has been known to cause excessive salivation,
sweating,bronchial mucus secretion, bronchospasm, bradycar
dia, vasodilation, and diarrhea. Eye drops can result in
brow ache and chronic use in miosis. Reports showed an
incidence of 65% for sweating in 31 patients treated with
pilocarpine 5mg 3 times daily for 5months.45 However, no
patients withdrew from therapy as a result of excessive
sweating.Systemic injection of pilocarpine can compromise
the blood brain barrier allowing pilocarpine to gain access to Fig. 5. structure of caffeine

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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

Toxicity of caffeine and adopted as raw materials for pharmaceutical

manufacturing. To date, more than 70 traditional and modern
Whether or not caffeine which can result in an addictive techniques are applied for processing Aconitum roots for
disorder depends on how addiction is defined. Compulsive medicinal use. In recent years, a large number of studieshave
caffeine consumption under any circumstances has not been investigated the toxicological and
observed, and caffeine is therefore not generally considered pharmacologicalcharacteristics of Aconitum, their main
addictive.63 However, some diagnostic models, such as alkaloids and their derivatives. The active components
the ICDM-9 and ICD-10, include a classification of caffeine of Aconitum have been reported to have significant
addiction under a broader diagnostic model.64 Some state that pharmacological and biological features.Different species of
certain users can become addicted and therefore unable to this genus exhibit antipyretic, anti-inflammatory, analgesic,
decrease use even though they know there are negative health astringent and anti-diarrheal activities. Besides, they also
effects.65, 66 Withdrawal can cause mild to clinically show strong antioxidant and antimicrobial activity. Effect of
significant distress or impairment in daily functioning. The several Aconitum alkaloids on central nervous system was
frequency at which this occurs is reported at 11%, but in lab screened by Ameri (1998) after dividing them in three
tests only half of the people who report withdrawal actually different groups comprising of highly toxic, less toxic and
experience it, casting doubt on many claims of reduced toxic alkaloids on the basis of their structure. It has
dependence.67 Mild physical dependence and withdrawal been reported that aconitine cause persistent activation of
symptoms may occur upon abstinence, with greater than Na+ channels in heart, skeletal muscles, CNS by blocking
100 mg caffeine per day, although these symptoms last no their inactivation.72 It has been reported that aconitine cause
longer than a day.68 Some symptoms associated persistent activation of Na+ channels in heart, skeletal
with psychological dependence may also occur muscles, CNS by blocking their inactivation.The initial
during withdrawal.69 Caffeine dependence can involve research focused on the cardiovascular (arrhythmogenic)
withdrawal symptoms such as fatigue, headache, irritability, toxicity of Aconitum alkaloids and especially AC. The
depressed mood, reduced contentedness, inability to marked cardiac activity of diterpene alkaloids is mainly due to
concentrate, sleepiness or drowsiness, stomach pain, and joint their effect on the voltage-gated Na+ channels.73
pain.70, 71 Death from caffeine ingestion appears to be rare.
This rarity may be related, in part, to the marked gastric
irritation from caffeine that results in spontaneous emesis.
Nevertheless, several hospitalizations and some deaths from
caffeine toxicity have been reported. For example, between
2005 and 2011, there were 79,438 emergency room visits
attributable to overconsumption of energy products containing
high levels of caffeine in patients aged 12 years and older.69

Aconitine
Fig. 6. structure of Acontine
Aconitine is an alkaloid toxin produced by the Aconitum
plant, it is also known as devil's helmet or monkshood.
Monkshood is notorious for its toxic properties. In China, Biosynthesis of aconitine
aconitine is also used in small doses as an analgesic and blood
coagulant.The medicinal plant species of Aconitum are a rich Aconitine is naturally synthesized by the monkshood plant via
source of alkaloids and flavanoids, many of which exhibit the terpenoid biosynthesis pathway (MEP chloroplast
broad spectrum of activity. Also isolated and identified are pathway). Approximately 700 naturally occurring C19-
various polysaccharides and free fatty acids. The diterpenoid alkaloids have been isolated and identified, but
pharmacological analysis of Aconitum species and their the biosynthesis of only a few of these alkaloids is well
compounds have shown various therapeutic effects. The key understood. Likewise, only a few alkaloids of the aconitine
points of the scientific research have been the effects of the family have been synthesized in the laboratory.
diterpene alkaloids on the central nervous system and the
heart. Their antimicrobial and cytotoxic effects have also been Toxicity of aconitine
studied. As a widely used Chinese herbal medicine, the tubers
and roots of Aconitum (Ranunculaceae) are commonly The toxic effects of aconitine have been tested in a variety of
applied for various diseases, such as collapse, syncope, animals, including mammals (dog, cat, guinea pig, mouse, rat
rheumatic fever, painful joints, gastroenteritis, diarrhoea, and rabbit), frogs and pigeons. Depending on the route of
oedema, bronchial asthma, various tumours, and some exposure, the observed toxic effects were: local
endocrinal disorders like irregular menstruation. However, the anesthetic effect, diarrhea, convulsions, arrhythmias or death
cardio and neurotoxicities of this drug is potentially lethal, .74 According to a review of different reports of aconite
and the improper use of Aconitum in China, India, Japan and poisoning in humans, hypotension, palpitations, chest pain
some other countries still results in a high risk of severe , bradycardia, sinus tachycardia, ventricular ectopics and other
intoxications. Based upon the regulations stipulated by the arrhythmias, ventricular arrhythmias, nausea, vomiting,
State. Food and Drug Administration of China, only the abdominal pain, and diarrhea are the major side-effects of
processed, detoxified tubers and roots of Aconitum are aconitine. Others include dizziness, hyperventilation,
allowed to be administered orally, used in clinical decoctions

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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

sweating, difficulty breathing, confusion, headache, Biosynthesis of harmine

and lacrimation.75
The Shikimate acid pathway yields the aromatic amino acid,
Harmine L-tryptophan. Decarboxylation of L-tryptophan by aromatic
L-amino acid decarboxylase (AADC) produces tryptamine (I)
The use of harmine as a multi-purpose traditional medicine containing a nucleophilic center at the C-2 carbon of the
has been translated into several commercial applications and indole ring due to the adjacent nitrogen atom that enables the
it is a highly valued phytoconstituent in the natural health, participation in a mannich-type reaction. Rearrangements
food and research area. Harmine has many traditional enable the formation of a Schiff base from tryptamine, which
medicinal uses and pharmacological activity such as then reacts with pyruvate in II to form a β-carboline
antimicrobial, anti-HIV and antiparasitic properties. Scientific carboxylic acid. The β-carboline carboxylic acid subsequently
studies conducted and verified many of the traditional uses undergoes decarboxylation to produce 1-methyl β-
including anti-inflammatory, antimicrobial, anti-parasitic and carboline III. Hydroxylation followed by methylation
anti-cancer effects. Harmine has the ability to stimulate in IV yields harmaline, the oxidation of harmaline is
dopamine release in the brain. Dopamine is a neurotransmitter accompanied by the loss of water and effectively generates
responsible for sending signals to the nerve cells.Harmine harmine.
possesses anxiolytic, behavioral effects and anti-tumor
potential both in vitro and in vivo.76 It has some dual Toxicity of harmine
effectson the upstroke of the action potential of atrial
muscle.77 Pharmacological activities ofharmine against Oral or intravenous harmine doses ranging from 30–300 mg
several microorganisms have been investigated and no have caused agitation, bradycardia or tachycardia, blurred
remarkable inhibitory activity against all the tested organisms vision, hypotension, paresthesias and hallucinations. It has
was reported except in Fusarium moniliforme.Harmine and recently been shown in the Journal of Photochemistry and
substances containing it have been used in conjunction with Photobiology that beta-carboline alkaloids such as harmine,
many other drugs in various scientific experiments,it is also a bind with DNA and also exhibit anti-tumor properties.
useful fluorescent pH indicator. Harmine is currently the only Harmine has been shown to bind one hundred times more
known drug that induces rapid mitosis and mass growth of effectively than its close analogue harmaline. The
pancreatic alpha (α) and beta (β) cells in adult humans. consequences of this are currently not well understood.78
These cells (alpha and beta) are normally very resistant to
growth stimulation in the adult stage of a human's life, as the Extraction of Alkaloids
cell mass is optimum at around age 10 and remains
unchanged from there on. Other similar drugs have been Due to the structural diversity of alkaloids, there is no single
successful in triggering beta cell proliferation method of their extraction from natural raw materials.79 Most
in rats/mice and pigs, however these drugs were met with methods exploit the property of most alkaloids to be soluble
very limited to no success in human subjects. in organic solvents but not in water, and the opposite
Harmine was found to increase the diminished beta cell tendency of their salts. Most plants contain several alkaloids.
mass of diabetic people to clinically significant levels for a Their mixture is extracted first and then individual alkaloids
short time: this property proves very useful in a possible are separated.81,82 Plants are thoroughly ground before
harmine-based treatment for both Type 1 and Type extraction.79, 80 Most alkaloids are present in the raw plants in
2 Diabetes. It is known to be a potent inhibitor of the form of salts of organic acids.80
the DYRK1A enzyme pathway and this is thought to be the
main mechanism by which harmine can induce alpha and beta Extraction with base
cell proliferation in vivo. DYRK1A is an enzyme that plays a
definitive role in suppressing/regulating cell proliferation, Base extraction is achieved by processing the raw plant
therefore it understandable that the partial blocking of material with alkaline solutions and extracting the alkaloid
DYRK1A increases the growth of certain cells, including bases with organic solvents, such as 1,2-dichloroethane,
pancreatic α and β cells. chloroform, diethyl ether or benzene. Then, the impurities are
dissolved by weak acids; this converts alkaloid bases into
salts that are washed away with water. If necessary, an
aqueous solution of alkaloid salts is again made alkaline and
treated with an organic solvent. The process is repeated until
the desired purity is achieved.

Extraction with water or acidic water

Alkaloids are alkaline and are present in salt form in the plant
and they can be extracted with water or acidic water. Usually,
Fig. 7. structures of harmine
inorganic acidic extraction is used, so that the organic acid of
alkaloids salt is replaced by inorganic acid salt increasing its
solubility. Acid extraction methods usually use 0.1% to 1%
sulfuric acid, hydrochloric acid or acetic acid, tartaric acid
solution as a solvent.81 The advantage of that acidic extraction

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H. Louis et al Journal of Medicinal and Chemical Sciences Original Article

is changing alkaloids molecules into small molecule organic Separation by Precipitation method
acid salts of inorganic acids, increasing the solubility in water,
and the extraction method is relatively simple. However, the We can use precipitation reagent precipitate Water-soluble
main drawback of this method is the need for more extraction alkaloids from the aqueous solution, and separate water-
solution, difficulty concentrating, and presence of water- soluble impurities which are remaining in the filtrate, in order
soluble impurities. to obtain higher purity water-soluble alkaloids or salts.
Commonly, Reye ammonium salt precipitation reagent in the
Extraction of alcohol solvent laboratory is used.

Both free alkaloids and alkaloid salts which can be dissolved Separation by simple extraction method
in methanol, ethanol, alcohol reflux, percolation or immersed
can be used to extract them. The advantage of alcohol If the desired ingredients are fat-soluble, organic solvents
extraction is that different alkaloids or alkaline salts can be such as benzene, chloroform or ethers can be with water
suited, in addition to the water-soluble impurities such as conducting liquid-liquid extraction to remove water-soluble
polysaccharides, proteins are less extracted. But its drawback ingredients such as sugars and inorganic salts. If the desired
is that more fat-soluble impurities are co extracted. Acidic ingredients are hydrophilic substance, the water solution can
water- alkaline - extraction methods can be used to remove be extracted with the weak lipophilic solvents such as ethyl
fat-soluble impurities using appropriate lipophilic organic acetate, butanol, pentanol acetate. The extraction and
solvent such as chloroform, benzene, ether and methylene separation of alkaloids to obtain active ingredients by liquid –
chloride to extract and recover solvent.79 liquid extraction method is often done according to the
differences of the nature of active ingredients or in
Extraction with acid coexistence of impurities as certain type of component
distribution coefficient which changed significantly with
In the acidic extraction, the raw plant material is processed by some methods.79
a weak acidic solution (e.g., acetic acid in water, ethanol, or
methanol). A base is then added to convert alkaloids to basic Fractionation method
forms that are extracted with organic solvent (if the extraction
was performed with alcohol, it is removed first, and the For the separation of the system of immiscible liquids,
remainder is dissolved in water). The solution is purified as different boiling points can be used for fractionation, and then
described above.81 refining and purification, this method is often used in the
volatile oils and purification of liquid alkaloids. To prevent
Seperation and Purification of Alkaloids some of the ingredients in the volatile oil being destroyed
when boiling, vacuum distillation is often used. In general, the
Generally, medical plants which often contain a variety of boiling point of the liquid mixture is above 100 ℃, the
alkaloids, mostly obtained by extracting, are a mixture of solution can be repeatedly fractionated several times to
alkaloids. Alkaloids are separated from their mixture using achieve the purpose of separation. If the difference of the
their different solubility in certain solvents and different boiling point is below 25℃, the use of fractionating column is
reactivity with certain reagents or by distillation according to needed.
the solubility of different alkaloids or alkaloid salt. Each
monomer of total alkaloids has different polarity, their Conclusion
solubility varies in an organic solvent and the difference can
be used to separate the alkaloids. Considering the importance of the drugs from the natural
sources, a new era has been developed in which synthetic
Separation According to Special Functional Group Present drugs are replaced to a great extent by the herbal medicines
due to the serious side effects associated with the use of
Some alkaloid molecules contain phenolic hydroxyl or synthetic drugs. Nature has blessed us with numerous types of
carboxyl group such as Lactone or lactam structure, these medicines from plants, animals, marine sources and microbes
groups or structures can occur in reversible chemical reaction, and they are gaining more and more importance in the field of
so they can be used for separation. Phenolic alkaloids form a novel drug discovery.Isolation and purification of alkaloids is
salt which are soluble in water in alkaline conditions, so they the key and the most difficult aspect of herbal medicine
can be separated from the general alkaloids. For example, in research and development.Besides, some of the traditional
the opium alkaloids, morphine has phenolic hydroxyl and separation and purification technology problems are low yield
codeine possess no phenolic hydroxyl, with sodium hydroxide and high cost of purification. This review gives an overview
solution treating opium alkaloids solution; morphine forms on pharmacological importance of named alkaloids,
salt and dissolves and codeine precipitates, so the two can be toxicology and methods of extraction and purification of plant
separated. Lactone or lactam structure alkaloids can be alkaloids which may be useful for researchers to investigate
saponified by heating in an alkaline aqueous solution to the medicinal potentials of these alkaloids and may also help
generate open-loop and form carboxylic acid salt which is in the development of new drugs for the treatment of various
water-soluble, so can separate from other alkaloids, they can diseases.
synthesize primary alkaloids and precipitate in acid
conditions.81 Reference

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How to cite this article: Hamzat T. Adejoke, Hitler Louis*, Oluwatobi O. Amusan, Gloria Apebende.
A Review on Classes, Extraction, Purification and Pharmaceutical Importance of Plants Alkaloid,
Journal of Medicinal and Chemical Sciences, 2019, 2(4), 130-139. Link:
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