Pharmaceutical Sciences

PHARMACEUTICAL SCIENCES

Subject : Pharmaceutical Sciences

(For Under Graduate Students)

Paper No. : B. Pharm VIIIth Sem

Paper – 38
Herbal Drug Technology

Topic No. & Title : 451:

Alkaloids – I: Chemistry, Biogenesis and
Pharmacological Activity of Atropine and
Related Compounds, Quinine, Reserpine

Academic Script

ALKALOIDS
Alkaloids are a chemically heterogeneous group of basic nitrogen containing
substances found predominantly in higher plants and also occur in lower plants,
animals, microorganisms and marine organisms. Alkaloids usually contain one or two
nitrogen atoms although some like ergotamine may contain up to five nitrogen
atoms. The term alkaloid was coined in 1819 by the pharmacist Meissner and meant
simply alkali-like molecules.' True Alkaloids' were defined as compounds meeting the
additional four qualifications namely:
a) Nitrogen is a part of heterocyclic ring
b) The occurrence of compound is restricted to plant kingdom
c) The compound has complex molecular structure
d) The compound manifests significant physiological activity

Proto Alkaloid or Amino Alkaloid

These are simple amines in which the nitrogen is not in a heterocylic ring. sometimes,
they are considered as biological amines. They are basic in nature and prepared in
plants from amino acids. Examples of these alkaloids are mescaline, N, N-dimethyl
tryptamine, colchicines and ephedrine.

Pseudo Alkaloids
The term ‘Pseudo alkaloids’ includes mainly steroidal and terpenoid alkaloids and
purines. They are not derived from amino acids. They do not show many of the

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typical characters of alkaloid, but give the standard qualitative tests for alkaloids. The
examples of pseudo alkaloids are conessine and caffeine.

Classification of Alkaloids
The chemical classification of alkaloids is universally adapted and depends on the
type of heterocyclic ring structure present. It is usual to classify alkaloids according to
the amino acids (or their derivatives) from which they arise. Thus the most important
classes are derived from the amino acids ornithine and lysine; or from the aromatic
amino acids phenylalanine and tyrosine; or from tryptophan and a moiety of
mavelonoid origin; and a number of compounds are also derived from anthranilic
acid or from nicotinic acid.

Examples of Alkaloids related various chemical classes:

a) Pyrrolidine group: hygrine, cuscohygrine, nicotine
b) Pyridine group: piperine, coniine, cytisine, lobeline
c) Quinoline group: quinine, quinidine, strychnine, brucine
d) Isoquinoline group: opium alkaloids (papaverine, morphine, codeine),
berberine, emetine,
e) Indole group:
i. Tryptamines: serotonin, bufotenine, psilocybin
ii. Ergolines (the ergot alkaloids): ergine, ergotamine, lysergic acid
iii. Beta-carbolines: harmine, harmaline, tetrahydroharmine
iv. Yohimbans: reserpine, yohimbine
v. Vinca alkaloids: vinblastine, vincristine
vi. Kratom (Mitragyna speciosa) alkaloids: mitragynine, 7-
hydroxymitragynine
vii. Tabernanthe iboga alkaloids: ibogaine, voacangine, coronaridine
f) Tropane group: atropine, cocaine, ecgonine, scopolamine
g) Phenethylamine group: mescaline, ephedrine, dopamine
h) Purine group:
i. Xanthines: caffeine, theobromine, theophylline

PROPERTIES OF ALKALOIDS
Physical Properties of Alkaloids
a) Alkaloids are well defined crystalline substances which unite with acids to form
salts.
b) In addition to the elements carbon, hydrogen and nitrogen, most alkaloids
contain oxygen; exceptions are coniine from hemlock and nicotine from
tobacco, are oxygen-free and are liquids.

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c) Generally the alkaloids are colorless but rare are colorful eg. Berberine is
yellow and salts of sanguinarine are copper-red.
d) The free bases of alkaloids are sparingly soluble in water but soluble in organic
solvents.
e) There are some exceptions to the above generalizations, eg. Caffeine (base)
being readily extracted from tea with water and colchicines being soluble in
either acid, neutral or alkaline water. Also some alkaloidal salts are sparingly
soluble for e.g. quinine sulphate is only soluble to the extent of 1 part in 1000
parts of water, although 1 part quinine hydrochloride is soluble in less than 1
part of water.

Chemical Properties of Alkaloids

a) Most of the alkaloids are basic in reaction, due to availability of lone pair of
electrons on nitrogen
b) The basic character of the alkaloid compound is enhanced if the adjacent
functional groups are electron releasing.
c) The alkaloid turns to be neutral or acidic when the adjacent functional groups
are electron withdrawing like amide group which reduces the availability of the
lone pair of electrons.
d) The alkaloids exhibiting basic character are very much sensitive to
decomposition and cause a problem during their storage.
e) The alkaloids may contain one or more number of nitrogen and it may exist in
the form as primary (R-NH2), e.g. mescaline
Secondary amine (R-NH) e.g. ephedrine
Tertiary amine (R3-N) e.g. atropine
Quaternary ammonium compounds [R4N+X] e.g. tubocurarine chloride
The quaternary ammonium compounds vary in properties from alkaloids, due
to quaternary nature of nitrogen.

TEST FOR ALKALOIDS

Qualitative test of Alkaloids
Alkaloids are detected by the use of different reagents. The composition of reagents
and color of precipitate:
a) Hager’s Reagent Test: It is a saturated aqueous solution of picric acid.
Inference: With alkaloids it shows yellow precipitate
b) Mayer’s Reagent Test: To prepare the reagent, 1.36 gm of mercuric chloride is
dissolved in distilled water. In another part dissolve 5gm of potassium iodide in
60 ml of distilled water. Then both the parts were mixed and the volume was
adjusted to 200 ml.

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Inference: With alkaloids it shows white to buff precipitate

c) Wagner’s Reagent Test: It is prepared by dissolving 1.27 gm of Iodine and 2 gm
of Potassium Iodide in 5ml of water and the final volume is made up to 200 ml.
Inference: With alkaloids it shows reddish brown precipitate
d) Dragendroff’s Reagent Test: To prepare this reagent, 14 gm of sodium
iodide was boiled with 5.2 gm of bismuth carbonate in 50 ml glacial acetic acid
for few minutes. Then it was allowed to stand for overnight and the precipitate
of sodium acetate was filtered out. To 40 ml of filtrate 160 ml of acetate and 1
ml of water was added. The stock solution was stored in amber-colored bottle.
During experiment; to 10 ml of stock solution 20 ml of acetic acid was added
and the final volume was made up to 100 ml with water.
Inference: With alkaloids this reagent gives orange-brown colored precipitate

Role of alkaloid in plants

The alkaloids are poisonous in nature, but when used in small quantities, exert useful
physiological effects on animals and human beings and hence they have secured
significant place in medicine. They are synthesized by a particular, stereospecific,
many a time complicated and energy consuming pathways and further they are
metabolizes to other alkaloidal or non alkaloidal substances. Some of the roles of
alkaloids in plants are as follows:
a) They are the reserve substances with an ability to supply nitrogen
b) They might be the defensive mechanisms for plants growing in dry regions to
protect from grazing animals, herbivores and insects.
c) It is also possible that they are end products of detoxification mechanism in
plants
d) They might have a possible role as growth regulatory factors in the plants.
e) They are present normally in conjugation with plant acids like meconic acid,
cinchotannic acid, etc. Therefore, alkaloids could be acting as carriers within
plants for transportation of such acids.

Biogenesis of Alkaloids
The living plants are considered as biosynthetic laboratory not only for the primary
metabolites likes sugars, amino acids and fatty acids that are utilized as food by man,
but also for a multitude of secondary products of pharmaceutical significance such as
glycosides, alkaloids, flavonoids, volatile oils, etc. the metabolites are of two types
Primary Metabolites: These are substances that are widely distributed in nature,
occurring in one form or another in virtually all organisms and are needed for general
growth and physiological development, because of their basic cell metabolism.

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Secondary Metabolites: These are biosynthetically derived from primary

metabolites but are more limited in distribution, usually being restricted to a
taxonomic group. They may represent chemical adaptations to environmental
stresses, or they may serve as defensive, protective or offensive chemicals against
microorganisms, insects and higher herbivorous predators.
The production of secondary metabolites is mostly dependent on the genetic on the
genetic makeup which selectively excel in one or another fundamental process
involved in the biosynthesis of such metabolites. These genetically controlled
fundamental processes can be termed as basic metabolic pathways.

Atropine
Plant source of atropine: Atropine obtained from the herb Belladona.
Biological source: Belladona herb consists of dried leaves or the leaves and other
aerial parts of Atropa belladonna (European belladona) or Atropa acuminata (Indian
belladona) or mixture of both the species collected when the plants are in flowering
condition. It belongs to family Solanaceae.
Geographical source: It is indigenous to and cultivated in England and other
European countries. In India, it is found in Western Himalaya from Simla to Kashmir
and adjoining areas of Himachal Pradesh.
History: Because of the hallucinogenic effect of this plant, it was used as witch craft
in the middle ages. In ancient times, the juice of this plant was used as a cosmetic,
because of its dilatory effect on the pupil of the eye.
Cultivaion and collection: Belladona berries are crushed to get the seeds for
cultivation. Proper processing like washing and sieving is performed. Only healthy
seeds are used for cultivation. Seeds are sown broadcasting method in well prepared
beds with the application of fungicide like diathon. Sowing is done in May and July.
The seedlings are ready for transplantation by the end of September. Transplanting is
done by keeping certain distance between two plants and the seedlings are irrigated
carefully. Fertilizers like urea, potash and superphosphate are given as per the needs.
The leaves as well as the flowering tops are cut and sundried or dried in shade.
During drying care is taken to retain the green color. While grading and packing for
market, wooly stems and foreign organic matter are rejected.
Macroscopic Characters:
Color - Leaves- Green to brownish-green
Flowers- Purple to yellowish-brown
Fruits- Green to brown
Odor - Slight and characteristic
Taste -Bitter and acrid
Size - Leaves- 5 to 25 cm long and 2.5 to 12 cm wide

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Flowers- Corolla 2.5 cm long and 1.5 cm wide

Fruits- About 10 cm in diameter
Shape - Leaves- Ovate, lanceolate to broadly ovate, with
acuminate apex, decurrent lamina, entire margin,
petiolate, brittle and transversely broken
Flowers- Campanulate, 5 small reflexed lobes of corolla
Fruits- Berries, sub-globular in shape with numerous flat
Seeds
Biogenesis of Atropine: Atropine belongs to tropane alkaloids group. The principal
alkaloids of medicinal interest in this group are (-)-hyoscyamine; its more stable
racemate is atropine and hyoscine (scopolamine). The compounds are esters and are
hydrolysed by heating at 60°C with baryta water. The atropine yields tropic acid and
tropine. Hyoscine gives tropic acid and oscine. Phenylalanine is the precursor of
tropic acid. Phenylalanine after transamination converts into phenyl pyruvic acid.
Phenyl pyruvic acid converts into tropic acid. Tropic acid and tropine forms levo
hyoscyamine. Levo- hyoscyamine converts into dextro– hyoscyamine and the
racemate is atropine.

Pharmacological Activity of Atropine: Atropine and hyoscyamine have the same

activity as parasympatholytics. Hyoscyamine has a stronger activity than racemic
atropine, but it is the latter that is commonly prepared and use. Atropine is an
inhibitor of the muscarinic receptors of the peripheral organs innervated by the
parasympathetic post-ganglionic fibers, and of central nervous system. It acts by
competitive and reversible inhibition of acetylcholine binding onto its receptors and
this antagonism leads, in the organs in question, to sympathomimetic-like effects.
a) It has stimulant action on CNS & depresses the nerve ending to the secretor
glands.
b) It is useful in ophthalmic products because it dilates the pupil of eye
(mydrasis).
c) Antispasmodic action –GIT motility is inhibited & gastric secretion is inhibited.
d) Cardiovascular System –alters heart rate, stimulation of vagus nerve,
bradycardia.
e) Inhibition of secretion –salivary, lachrymal, bronchial, & scrotal gland
producing an uncomfortably dry mouth & skin.

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QUININE
Plant source of quinine: Quinine obtained from the cinchona bark.
Biological source: Cinchona is the dried bark of the cultivated trees of Cinchona
calisaya, Cinchona ledgeriana, Cinchona officinalis, Cinchona succirubra, or of hybrids
of either of the last two species with either of the first two. Cinchona belongs to
family Rubiaceae.
Geopgraphical Source: It is found in India, Bolivia, Columbia, Ecuador, Peru,
Tanzania, Guatemala, Indonesia, and Sri Lanka. In India, it is found in Annamalai hills
and Nilgiri hills in Tamil Nadu and in Darjeeling area of West Bengal.
History: The name Cinchona is said to be derived from a Conutness of Chincon, wife
of a viceroy of Peru who it was long believed was cured in 1638 from a fever by the
use of the bark. It was officially reported in London Pharmacopoeia in 1677. After the
isolation of quinine and cinchonine in 1820 by Pelletier and Canventon, the alkaloids
or their mixtures came into use as a medicine. In 1860, Cinchona calisaya, Cinchona
micrantha and Cinchona succirubra were introduced in India by Markham. In India,
owing to the antimalarial and antipyretic use of this drug, right from 1880, a large
area was taken for cultivation of cinchona in West Bengal, which eventually shifted to
South India.
Cultivaion and collection: Most of the cinchona species profusely grow in sub-
tropical or tropical climates at a height of about 1000-3000 meters. The propagation
is done with either seeds or budding or layering. In West Bengal, only budding is
practiced and in Tamil Nadu, the budding and layering methods are applied. The
seeds of cinchona are very small and light in weight. They are admixed with soil
during sowing. The maintenance of genetic purity causes a problem as high cross
fertilization occurs in cinchona plants. This affects the yield, like in high alkaloid
content giving species, such as C. ledgeriana, the average alkaloid content is reduced.
The seeds should be immediately used for propagation as on storage they lose their
viability. The germination takes place in 3-6 weeks. The seedlings with 2 pairs of
leaves are transplanted and space of 6-10 cm is maintained in between two seedlings
and 2 rows. The young seedlings are protected from direct sunlight. In forest soil,
they are transplanted after 15 months of growth and preferably before heavy rain
fall. A distance of 2X2 meters is maintained between two plants. As cinchona consists
of stem, as well as root bark, the plants from 4-20 years of age are selected for
harvesting, but the maximum alkaloidal content is found to 6 to 10 years old plants.
The bark is collected by coppicing method. For this purpose, vertical incisions are
made on branches, trunk of tree and these incisions are connected by horizontal
circles. The bark is then stripped off and dried in sun light and further by artificial
heat. During drying, the bark loses upto 70% of its weight. The care should be taken
to avoid molding or fermentation during drying. The quills of drug are packed in

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gunny bags and marketed. The root bark is collected by uprooting the trees and bark
is separated manually.

Macroscopic Characters:
a) Stem bark: The commercial quills are up to 30 cm long and usually 2-6 mm
thick. Bark for manufacturing purposes is frequently in small curved pieces.
The outer surface frequently bears moss or lichen. The cork may or may not be
longitudinally wrinkled, and usually bears longitudinal and transverse cracks,
which vary in frequency and distinctness in different varieties. The inner
surface is striated and varies in color from yellowish-brown to deep reddish-
brown. The fracture is short in the outer part but somewhat fibrous in the
inner part. Odor, slight; taste, bitter and astringent.
b) Root bark: Root-bark occurs in channeled, often twisted pieces about 2-7 cm
long. Both surfaces are of similar color, the outer however, being somewhat
scaly, while the inner surface is striated.

Biogenesis of Quinine: The biogenesis of quinine and related alkaloids of cinchona

proceeds through a routine indicating transformation of indole to quinoline. In
regard with the source of non-tryptamine derived portion, however, participation of
a monoterpene glucoside, secologanin from mevalonate-pathway. The most
significant feature of quinine biosynthesis is cleavage of benzypyrrole ring of
trptophan moiety and rearrangement to form the quinoline nucleus.
Trptophan and its decarboxylation product tryptamine, serve as the precursors for
biosynthesis of a large class of indole alkaloids. The nontryptophan portions of
alkaloids are, however, derived from monoterpenoid precursors which are
designated as Coryanthe, Iboga and Aspidosperma types. The reactive form of
terpene involves an aldehyde group. The loss of one carbon atom during biogenesis
to give C9 unit appears to be largely common. It is belived that Coryanthe type
monoterpenoid moiety is metaboloically most primitive. Condensation of tryptamine
(or trptophan) with secologanin, a monoterpene glucoside, gives rise to a
nitrogenous glucoside, vincoside, from which a great variety of indole alkaloids.
Vincoside converts to geissochizine then to coryantheal. Corynantheal converts to
cinchonidinone and finally converts into quinine.
Pharmacological Activity of Quinine: Quinine is an antimalarial. It is active on the
erythrocytic forms, up to the young trophozoite stage (in vitro, older trophozoites
and schizonts are resistant). It is active on Plasmodium vivax, falciparum, malariae
and ovale, inactive on the sporozoites and the tissue stages and practically inactive
on the gametocytes.

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The action of quinine on the myocardium, as well as of quinidine, but to a lesser

extent, is a decrease in excitability, conductibility and contractility. Quinine is only
modestly antipyretic and analgesic; it has a weak curare - type activity on the motor
end – plate.

RESERPINE
Plant source of Reserpine: Reserpine obtained from the plant Rauwolfia.
Biological source: Rauwolfia consists of dried roots of the plant known as Rauwolfia
serpentine, belonging to family Apocynaceae.
Geographical source: Several species of Rauwolfia are found distributed in the
tropical regions of Asia, America and Africa. Commercially, it is produced in India, Sri
Lanka, Myanmar, Thailand and America. In India, it is cultivated in U.P., Bihar, Orissa,
Tamil Nadu, West Bengal, Karnataka, Maharashtra and Gujarat.
History: This drug is known to Indian System of Medicine since last many centuries.
Because of snake like shape of the drug; it has been known as ‘Sarpagandha’. It has
found its place as an important drug in treatment of insanity and snake bite since
traditional times.
Cultivation and collection: This collected from wild as well as cultivated species. In
wild state, it grows in variety of soils. But for cultivation, clay loamy soil with large
amount of humus and good drainage are supposed to be ideal. The temperature
range for cultivation is 10° C to 38° C. Rainfall should be in the range of 250-500cm. It
can be propagated by various methods, such as by seeds, roots, cutting, root stumps,
etc. the propagation from seeds is usually the method of choice. The healthy seeds
are sown into the nursery beds. The rate of germination of seeds is very low, hence
sufficient quantity of the seeds are sown. Sowing is done in the month of May or at
the break of monsoon. The seedlings are then transplanted in the month of August at
a distance of 16 to 30 cm. The plants are provided with various chemical fertilizers
and manures. The plants are kept free from weeds. When the plants are about 3 to 4
years old, they are uprooted. The roots are cut properly, washed so as to remove the
earthy matter and dried in air.
Macroscopic characters:
Color - Root bark is grayish yellow to brown and wood, pale
yellow
Odor - Odorless
Taste - Bitter
Size - About 10 to 18 cm long and from 1 to 3 cm in diameter
Shape - Roots are sub-cylindrical, slightly tapering, tortuous
Surface - The transversely cut surface is white, dense with finely
radiating xylem

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Fracture - Short and irregular

Biogenesis of Reserpine: Tryptophan and its decarboxylation product, tryptamine,

give rise to the large class of indole alkaloids. These bases usually contain two
nitrogen atoms; one is the indolic nitrogen and the second is generally two carbons
removed from the beta position of the indole ring. The more complex indole alkaloids
contain a nontryptophan-derived portion of the molecule and this is supplied by
mevalonic acid. Then it forms lysergic acid, resepine and strychnine. The lysergic acid
converts into ergot alkaloid.

Pharmacological Activity of Reserpine: Reserpine lowers the blood pressure by

depleting stores of catecholamines at nerve endings. It prevents no re-uptake of or
epinephrine at storages sites, allowing enzymatic destruction of neuronal
transmitter. It is used to treat mild essential hypertension and may be an effective
adjunct to the treatment of more severe hypertension. Because of the tranquillising
effects, the drug is used in mild anxiety conditions and reserpine in some of the
neuropsychiatric disorders.

Reserpine is currently of secondary interest, although it was formerly widely used,

beginning in 1960s, for its neuroleptic properties and mostly for its antihypertensive
activity. By causing an peripheral catecholamine depletion, this alkaloid induces a
lasting drop in blood pressure and heart rate. The central neurotransmitter depletion
would explain its sedative and neuroleptic activity.

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