Alkaloids

Alkaloids

Alkaloids are defined as a group of secondary

metabolites of plant, microbial or animal origin that
contain nitrogen atom (except proteins, peptides, amino
acids and vitamin B).

They are nitrogen heterocycles which occur mainly in

plants as their salts of carboxylic acids like citric, oxalic,
acetic acids.

Their amine character produce an alkaline solution in

water and hence the origin of their name - alkaloids.
 Alkaloids
Properties of alkaloids:
In general, they are colorless, crystalline solids which
are basic, have a ring structure, and have definite melting
point.

They are secondary metabolites having bitter taste.

Most alkaloids are optically active, most of levo rotatory

but few are dextro rotatory e.g. conine.

They are nitrogenous organic molecule and has marked

physiological activities on humans and animals.
 Alkaloids

Generally, free bases of alkaloids are soluble in organic

solvents and insoluble in water, whereas alkaloidal salts
are soluble in water.

True alkaloids: They have a heterocyclic ring with one or

more nitrogen atom and are derived from amino acid. E.g.
atropine, quinine etc.
Proto alkaloids: They are also derived from
aminoacids but they do not have nitrogen in the
heterocyclic ring. E.g. ephedrine, colchicine etc.

Pseudo alkaloids: They have a heterocyclic ring with

nitrogen but they are not derived from amino acids.
E.g. caffeine, aconitine etc.
Classification of Alkaloids:
A. Pharmacological Classification:
In this classification alkaloids have been classified
according to their therapeutic values, eg.
Antimalarial: Quinine
Bronchodilator: Ephedrine
Anticancer: vinblastine and vincristine
Respiratory stimulant: lobeline
Narcotic analgesic: Morphine
Antitussive: Codeine
Cardiac depressant: Quinidine
B. Chemical Classification:
This classification is universally adopted and depends
on the fundamental ring structure.

1.Non-heterocyclic Alkaloids: In this group of

alkaloid not has any one heterocyclic ring in their
structure. e.g.- Hordinine (Hordeum vulgare),
Ephedrine(Ephedra gerardiana).

2.Heterocyclic Alkaloids: According to

heterocyclic ring the alkaloids are sub divide in
following groups:
Class Basic skeleton Examples

Pyrrole
Coca Spp.

(Hygrine, Stachydrine)
Pyrrolidine

Pyrrolizidine Senecio Spp.

(Senecionine)
Pyridine

Areca spp., Lobelia spp.

(Arecoline, lobeline)
Piperidine

Tropane Atropa spp.

(Atropine, hyoscyamine)

Quinoline Cinchona spp.

(Quinine, quinidine)
Isoquinoline Papaver spp.
(Papaverine, narcotine)

Aporphine
(Boldine)

Nor-lupinane (lupanine)

Indole Rauwolfia spp.

(reserpine, serpentine)
Indolizidine (Swainsonine)

Imidazole (Pilocarpine)

Purine (Caffeine)
C. Biosynthetic Classification:
The alkaloids derived from the same precursor have
been grouped into the same class.
Precursors Alkaloids

Ornithine Tropane, Pyrrolidine, Pyrrolizidine

Tyrosine Benzyl-isoquinoline
Tryptophane Indole, Quinoline

Pyridine Pyridine

Lysine Quinolizidine, Piperidine

 Alkaloids
Chemical Tests of alkaloids:
Mayer’s Test: Specimen with Mayer’s reagent give
cream or pale yellow ppt.
Dragendroff Reagent Test: Specimen with Dragendroff
reagent give orange ppt.
Wagner's Test: Specimen with Wagner’s reagent give
brown or reddish brown ppt.
Hager’s Test: Specimen with Hager’s reagent give
yellow ppt.
Ammonium Rinker Test:
Specimen with Ammonium rinket solutions with HCL give
flocculent pink ppt.
 Atropine

Atropine is solanaceous alkaloids found mainly in

Hyoscyamus niger, Atropa belladona (deadly nightshade)
and Datura stramonium (Jimson weed).

It is tropine ester of racemic tropic acid and is optically

inactive.

OR
 Atropine

The racemic form of hyoscyamine is called atropine.

Atropine as white, odorless crystals possessing a bitter

taste.
It is not very soluble in water but is more soluble in
alcohol.
 Atropine

Pharmacological effects:
Atropine produces a mydriatic effect by paralysing the
iris and ciliary muscle and hence used in iritis and corneal
inflammation and lesions.

Atropine possess anti-secretory activity so that it is used

to block secretions in upper and lower respiratory tracts
prior to surgery.

Atropine is used as an antispasmodic agent to relax the

gastrointestinal tract and bladder.
Biosynthesis of Atropine/hyoscyamine :

Methylation Decarboxylation

Oxidation

2 X AcetylCoA
 Cyclization
Decarboxylation

Reduction

Ester formation + rearrangement

 Hyoscine (Scopolamine)

Hyoscine is found in various members of solanaceae

family such as Hyoscyamus niger, Datura metel, Duboisia
myoporoides and Scopolia sp.

It is scopine ester of racemic tropic acid.

OR
 Hyoscine (Scopolamine)

Hyoscine occurs in the form of viscous liquid i.e.

slightly soluble in water but very soluble in alcohol,
chloroform, ether etc.

Hyoscine is also occurs in racemic form, its racemic

form being called as atroscine.

In contrast to atropine which stimulates the CNS,

hyoscine acts as CNS depressant hence, it is used as
preanaesthetic medicament.
 Hyoscine (Scopolamine)

Hyoscine is commercially available as transdermal

patches and is effective for the prevention of motion
sickness.

Hyoscine is also used as anti-spasmodic agent due to its

smooth muscle relaxant activity.
 Biosynthesis of Hyoscine/Scopolamine :

Ornithine putriscine

Hyoscyamine

O2/2-oxoglutarate
Hyoscyamine 6β-hydroxylase

O2/2-oxoglutarate

Hyoscine 6-Hydroxyhyoscyamine
 Hyoscine (Scopolamine)

Comparative features of atropine and hyoscine

 Quinine

Quinine is obtained from cinchona or peruvian bark of

the stem or root of Cinchona succirubra(red bark),
Cinchona calisaya (yellow bark), Cinchona ledgeriana
(brown bark) (Family: Rubiaceae).

Cinchona contain more than 30 closely related

alkaloids, among them quinine, quinidine, cinchonine and
cinchonidine are chiefly identified alkaloids.

The alkaloids are often present in the bark in salt

combination with quinic acid or a tannin material called
cinchotannic acid.
 Quinine
These constituents are the stereoisomers of each other
like quinine is stereoisomer of quinidine and cinchonine is
stereoisomer of cinchonidine.
Basic Structures
 Quinine

Quinine and quinidine has a methoxy group in it but

cinchonine and cinchonidine do not have a methoxy
group.

All cinchona alkaloids have 4-stereocenters namely C-

3,-4,-8 and -9.

Quinine occurs as a white odorless bulky bitter crystals

or crystalline which darken on exposure to light.
 Quinine

Quinine is freely soluble in alcohol, ether and

chloroform but slightly soluble in water.

Uses:
Quinine is used for the treatment of multidrug-resistant
malaria, a disease caused by protozoa(Plasmodium
falciparum).

Quinine also has skeletal muscle relaxant effect. Hence,

can be use in the prevention and treatment of nocturnal leg
cramps.
 Quinine

Quinidine is used as a cardiac depressant (anti-

arrhythmic), particularly to inhibit auricular fibrillation.

Cinchonine and cinchonidine are used as anti-

inflammatory.
Biosynthesis of Quinine :

+
 Reserpine

Reserpine is obtained from the dried rhizomes and roots

of Rauwolfia serpentina (Apocyanaceae).

It is also obtained from the other species of Rauwolfia

such as R. canescens, R.vomitoria.

R. serpentina contains a wide range of indole alkaloids,

totalling about0.7-2.4% of which0.15-0.2% are
therapeutically active compounds, principally reserpine,
rescinnamine, and deserpidine.
 Reserpine

Other notable alkaloids are serpentine, ajmalicine, and

ajmaline.

Reserpine and deserpidine have been widely used as

antihypertensive and mild tranquillizers. They act by
interfering with catecholamine storage, depleting levels of
available neurotransmitters.

Reserpine or Rauwolfia alkaloids are now hardly used

as anti-hypertensives or as tranquillizers due to
availability of more promising synthetic alternatives.
 Reserpine

Reserpine has been suggested to play a role in

promotion of breast cancer.

Ajmalicine is used as an antihypertensives and ajmaline

is used in the treatment of cardiac arrhythmias.
Biosynthesis of Reserpine:

Homoallylic
isomerization
Reduction

1. Hydroxylation
2. + trimethoxybenzoyl Chloride
 Opium Alkaloids

Opium alkaloids are obtained from opium which is air

dried milky exudates or latex obtained form incised unripe
capsules of Papaver somniferum (Papaveraceae).

Opium contains numerous alkaloids (as meconates and

sulfates), of which morphine, codeine, noscapine
(narcotine) and papaverine are therapeutically the most
important.

They can be divided chemically into 2 distinct classes:

 Opium Alkaloids

Phenanthrenes: Morphine, Codeine, Thebaine.

Benzylisoquinolines: Papaverine, Noscapine.

 Morphine

Morphine is prototypic narcotic analgesic obtained from

the opium poppy (Papaver somniferum).

The free alkaloid occurs as levorotatory, odourless,

white, needle-like crystals possessing a bitter taste.

It is almost insoluble in water, ether, or chloroform;

somewhat more soluble in ethyl alcohol.

It is a monoacidic base and readily forms water soluble

salts with most acids.
 Morphine

As morphine itself is so poorly soluble in water, the salts

are the preferred form for most uses.

2
Phenolic hydroxy HO 3 1
group
4 11
12 10
Ether bridge O 15 16 Tertiary Nitrogen group
13 14 9 N
5
CH3
8 Alicyclic unsaturated linkage
Alcoholic hydroxy HO
6
group 7
 Morphine

Derivatives of morphine:

Codeine Thebaine Heroin

 Morphine

Uses of Morphine:
a) Analgesia:
One of the effective drug in the relief of pain.

Opioids induce sleep, and in clinical situations when

pain is present and sleep is necessary.

b) Treatment of diarrhea: Morphine decreases the

motility and increases the tone of intestinal circular
smooth muscle.

c) Relief of cough: Morphine suppresses the cough

reflex.
 Morphine

Codeine: Has a reputation as an antitussive, depressing

the cough reflex, and is used in many cough preparations.

Thebaine: It is almost devoid of analgesic activity, but

may be used as a morphine antagonist.

Heroin: It is widely used for terminal care, e.g. cancer

sufferers, both as an analgesic and cough suppressant.
Biosynthesis of Morphine:
 O2
NADPH

Radical
coupling

AcetylCoA Reduction
Demethylation

Demethylation

Reduction
 Papaverine

Papaverine is a benzyl isoquinoline alkaloid and

structurally different from morphine, thebaine and codeine
group of alkaloids (morphinans).

It is optically inactive alkaloids and doesnot contain any

chiral centre.
 Papaverine

It has little or no analgesic or hypnotic properties.

Its main effect is as spasmolytic on smooth muscle

acting as a direct non-specific relaxant on vascular,
cardiac and other smooth muscle.

It is sometime used as an effective treatment for male

impotence.

It has been used in some expectorant preparation and in

the treatment of gastrointestinal spasms.
Biosynthesis of Papaverine:

+
L-Tyrosine

SAM

Methylation Hydroxylation
Dehydrogenation Methylation
 Ephedrine

Ephedra or Ma Huang is one of the oldest known drugs,

having being used by the Chinese for at least 5000 years.

It consists of the entire plant or tops of various Ephedra

species(Ephedraceae), including Ephedra sinica and
Ephedra equisetina from China, and Ephedra
geriardiana, Ephedra intermedia and Ephedra major from
India and Pakistan.

The plants typically contain 0.5-2.0% of alkaloids,

according to species.
 Ephedrine

There are three pairs of optically active diastereomeric

alkaloids: (−)-ephedrine and (+)-pseudoephedrine, (−)-
methylephedrine and (+)-methylpseudoephedrine, and
(−)-norephedrine and (+)-norpseudoephedrine.
 Ephedrine

Typically, from 30 to 90% of the total alkaloids is (−)-

ephedrine.

Ephedrine has two asymmetric carbon atoms; thus there

are four optically active forms.
 Ephedrine

The erythro racemate is called "ephedrine" and the threo

racemate is known as "pseudoephedrine".

Ephedrine decomposes gradually and darkens when

exposed to light.

The pharmacological activity of ephedrine resembles

that of epinephrine and acts on both α- and β-adrenergic
receptors. Hence, have vasoconstrictive and CNS
stimulant actions.
 Ephedrine

Uses of ephedrine:
Ephedrine and its salts are used orally, intravenously,
intramuscularly, and topically for a variety of conditions
such as allergic disorders, colds and hypotensive
conditions.

It is used locally to constrict the nasal mucosa and cause

decongestion and to dilate the pupil.

Systematically, it is effective for the asthma and hay

fever.
Biosynthesis of Ephedrine:

Side chain degradation

via cinnamic acid
-CO2

Transamination

SAM Reduction
 Ergot Alkaloid

Ergot is the dried sclerotium of a fungus, Claviceps

purpurea (Clavicipitaceae), arising in the ovary of the rye
plant.

The poisonous properties of ergots in grain (rye) for

human or animal consumption have long been recognized,
and the causative agents are known to be a group of indole
alkaloids, referred as the ergot alkaloids or ergolines.

The ergot sclerotia contain from 0.15-0.5% alkaloids,

and more than 50 have been characterized.
 Ergot Alkaloid

The medicinally useful compounds are derivatives of

(+)-lysergic acid and can be separated into two groups:
a. Water-soluble amino alcohol derivatives (about
20% of the total alkaloids)

b. Water-insoluble peptide derivatives (about 80%

of total alkaloids).
 Ergot Alkaloid

a. Water-soluble amino alcohol derivatives:

Ergometrine is an amide of lysergic acid and 2-
aminopropanol, and is the only significant member of this
group.
 Ergot Alkaloid

b. Water-insoluble peptide derivatives:

These derivatives can be subdivided into three groups:
the ergotamine group, the ergoxine group, and the
ergotoxine group.
Ergot Alkaloid
 Ergot Alkaloid

Uses of Ergot Alkaloids:

Traditionally whole ergot preparations were used in
labour to assist delivery and to reduce post-partum
haemorrhage.

Ergometrine is uses as an oxytocic and is injected

during the final stages of labour and immediately
following the child birth. Bleeding is reduced due to its
vasoconstrictor effects.
 Ergot Alkaloid

Ergotamine and the semisynthetic dihydroergotamine

salts are used as specific analgesics for the treatment of
migraine.

Lysergic acid diethylamide (LSD-25) prepared by

partial synthesis from lysergic acid is a potent specific
psychotomimetic (treatment of Parkinson disease).
 Vinca Alkaloid

Vinca alkloids are obtained from Madagascar

periwinkle; Catharanthus reseus / Vinca roseus
(Apocynaceae).

The plant was originally investigated for potential

hypoglycaemic activity because of traditional usage as a
tea for diabetics.

Animal model experiment suggest no antidiabetic effect

but found to decrease WBC levels.
 Vinca Alkaloid

The selective action suggested anticancer potential for

the plant.

Around 150 alkaloids have been isolated from this plant,

they are principally terpenoid indole alkaloid.

The various dimeric indole alkaoids present in this

plants are vinblastine, vinleurosine, vinrosidine, and
vincristine.
 Vinca Alkaloid

The alkaloids vinblastine and vincristine were

introduced into cancer chemotherapy and have proved to
be extremely valuable drugs.
 Vinca Alkaloid

The alkaloids vinblastine and vincristine were

introduced into cancer chemotherapy and have proved to
be extremely valuable drugs.

Vinca alkaloids inhibits cell mitosis, acting by binding

to the protein tubulin in the mitotic spindle, preventing
polymerization into microtubules.

Vinblastine is used mainly in the treatment of

Hodgkin’s disease, a cancer affecting the lymph glands,
spleen, and liver.
 Vinca Alkaloid

Vincristine has superior antitumour activity compared

with vinblastine but is more neurotoxic. It is clinically
more important than vinblastine, and is especially useful
in the treatment of childhood leukaemia.

Vincristine can also be used in some other cancer

conditions, including lymphomas, small-cell lung cancer,
and cervical and breast cancers.