Tikrit university

College of pharmacy
Pharmacognosy III 3rd lec.

Quinoline nucleus

In general, the alkaloids containing essentially the ‘quinoline’ nucleus include a series of
alkaloids obtained exclusively from cinchona bark, the major members of this particular
group are, namely: quinine, quinidine, cinchonine and cinchonidine. Interestingly, more than
twenty five alkaloids have been isolated and characterized either from the Yellow Cinchona i.e.,
Cinchona calisaya, and Cinchona ledgeriana, or from the Red Cinchona i.e., Cinchona
succirubra (Family: Rubiaceae). However, it has been revealed that an average commercial
yield of the cinchona alkaloids in the dry bark materials from the said plant materials are as
follows:
quinine (5.7%)
quinidine (0.1-0.3%)
cinchonine and cinchonidine (0.2-0.4%). Nevertheless, the other closely related minor
alkaloids are present in relatively smaller quantities.
Basic Structures of Cinchona Alkaloids:
The various quinoline alkaloids, which possess potent medicinal activities, are
namely: quinine, quinidine, cinchonine, and cinchonidine.
These alkaloids possess the basic skeleton of 9’-rubanol that is derived from the parent
compound known as ruban. Thus, ruban is obtained from the combination of two distinct
heterocyclic nuclii, namely: 4-methyl quinoline nucleus, and (b) quinuclidine nucleus.

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However, this particular nomenclature was suggested by Rabe so as to simplify the naming of
such compounds and also to signify its origin from the natural order Rubiaceae.

A few important drugs belonging to the quinoline alkaloids shall now be discussed in the
sections that follow:

Quinine & quinidine are stereoisomers

Cinchonine & cinchonidine are stereoisomers

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For cinchonine & quinidine C8= R , C9 = S
For cinchonidine & quinine C8 = S , C9 = R

(Stereoisomers are isomeric molecules that have the same molecular formula and sequence of
bonded atoms (constitution), but that differ only in the three-dimensional orientations of their
atoms in space. This contrasts with structural isomers, which share the same molecular formula,
but the bond connections or their order differs. By definition, molecules that are stereo isomers
of each other represent the same structural isomer).

Quinine

Identification Tests
1. Fluorescence Test: Quinine gives a distinct and strong blue fluorescence when treated with
an oxygenated acid, such as: acetic acid, sulphuric acid. This test is very marked and
pronounced even to a few mg concentration of quinine.
Note: The hydrochloride and hydro iodide salts of quinine do not respond to this
fluorescence test.
2. Thalleioquin Test: Add to 2-3 ml of a weakly acidic solution of a quinine salt a few drops of
bromine-water followed by 0.5 ml of strong ammonia solution, a distinct and characteristic
emerald green color is produced. The colored product is termed as thalleioquin, the chemical
composition of which is yet to be established. This test is so sensitive that quinine may be
detected to a concentration as low as 0.005%.
Notes: Quinidine gives also a positive response to this test; but cinchoninine and cinchonidine
give a negative test.

Biosynthesis of Quinine

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 Quinine is biosynthesized from tryptophan through the formation of tryptamin which will
condense with secologanine to form strictosidine which will form quinine through corynanth.
The different steps are shown in the following steps:

Uses
Cinchona & its alkaloids have been used in the treatment of malaria fever for many years.
Quinine sulfate continues to be used for malaria in many parts of the world (it poison the
protozoa), as tonic, analgesic, in the treatment of cold.

Quinine was first recognized as a potent antimalarial agent hundreds of years ago. Since then,
the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and
hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in
addition to malaria. In recent years, antimalarials were shown to have various
immunomodulatory effects, and currently have an established role in the management of
systemic lupus erythematosus and rheumatoid arthritis, skin diseases and recently for Covid-19

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Quinidine is used to treat various cardiac arrhythmias e.g. arterial & ventricular tachycardia,
atria fibrillation & ventricular contraction. Quinidine is found as salts (sulfate & gluconate). It
depresses myocardial excitability, conduction velocity & contractility.

Totaquine
It is a mixture of total alkaloids, containing not less than 7% & not more than 12% of
anhydrous quinine. It should contain 70-80% of total alkaloids. It is used as anti malarial & for
cold but it cannot be used as cardiac depressant. Usual dose 600mg.

Cinchonism or quinism
Treatment with cinchona products result in symptoms of mild cinchonism (which may occur
from standard therapeutic doses of quinine) include flushed and sweaty skin, ringing of the ears
(tinnitus), blurred vision, impaired hearing, confusion, reversible high-frequency hearing loss,
headache, abdominal pain, rashes, dysphoria, nausea, vomiting and diarrhea. Ringing in the
ears is a symptom of toxicity. When these symptoms are produced as the result of continuous
use of cinchona or of quinine the condition has been called cinchonism.

Images of cinchona tree & bark

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ISOQUINOLINE ALKALOIDS

Within the alkaloids as a group, the isoquinolines have had a profound effect on
human society as agents for pain relief and as drugs of abuse. In particular, opium,
which is rich in morphinane-type isoquinolines, has been used for millennia in the
treatment of pain and as a narcotic substance and, arguably, no other substance has
caused so much human misery.
Opium is the gummy exudate of the unripe capsules of the opium poppy (Papaver
somniferum, Papaveraceae)
and contains more than 30 alkaloids, of which the major components are morphine,
codeine, thebaine, papaverine and noscapine ,The majority of opium, which is
produced for illegal drug use, now originates in Afghanistan. When the British
conquered the area of Bengal (now eastern India and Bangladesh) in the late 18th
century, they discovered an area rich in opium fields and, as at that point in time
there was a huge demand for Chinese tea, the opium was therefore used as a form
of currency. Unfortunately, the addictive nature of opium was not well known and
many Chinese became addicted through smoking the crude drug in opium dens
(which were also a part of London life in the 19th century). This generated a huge
social problem and resulted in war (opium war) between Britain and China.

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Image of Opium poppy

Morphine, derived from the name for the Greek god of sleep Morpheus, possesses
both a basic tertiary amine and an acidic phenol functional group. These groups
allow morphine to be readily purified by acids and bases; pure morphine was
produced in the 1880s and was rapidly recognized as an excellent analgesic when
injected (despite its addictive properties). Morphine is readily converted into the
drug of abuse, heroin (diamorphine), by acetylation of both hydroxyl groups using
acetic anhydride. Much has been written on the destructive nature of heroin as a
drug of abuse, but this agent is highly useful in the management of pain,
particularly in patients with terminal cancer.
Why morphine should dramatically affect analgesia in humans was a mystery until
the discovery that we also produce a natural endogenous morphine-like substance
(endorphin), which acts at the same site as morphine and is a pentapeptide (Tyr-
Gly-Gly-Phe-Met). This molecule, named metenkephalin (met being the terminal
methionine residue, and enkephalin being derived from the Greek for ‘in head’)
has a portion that shows striking similarity to morphine and explains why both
molecules bind to the opiate receptor. Morphine is used as a centrally acting
analgesic and as a smooth muscle relaxant.

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 Isolation The latex obtained by incision on the unripe capsule of opium poppy is
first collected in clean, plastic containers, and the process of incision is repeated at
least four times on the same capsule after an interval of two days. Care must be
taken to make the incisions on the superficial surface only so as to collect
exclusively the external exudation of latex. Subsequently, the latex is dried
carefully either by exposing to air on metallic shallow plates or by passing a stream
of hot air.
Thus the ‘opium’ or the dried latex is stored for the isolation of morphine. It is
found to contain usually 9.5% morphine when calculated as anhydrous morphine.
The morphine may be isolated from ‘Powdered Opium’ by adopting the
following steps sequentially:
Step-1: The powdered opium is shaken with calcium chloride solution and
filtered.
Step-2: The resulting filtrate is concentrated and to it is added 10% w/v sodium
hydroxide solution carefully i.e., to solubilize morphine, codeine and narceine. It is
now filtered.
Step-3: The filtrate containing morphine, codeine and narceine is extracted with
chloroform. The resulting mixture is separated.
Step-4: The lower chloroform layer contains codeine, whereas the upper
aqueous layer comprises of morphine and narceine.
Step-5: The aqueous layer is first acidified and subsequently made alkaline with
ammonia, whereby morphine gets precipitated and collected as a while solid
residue (Yield = 9.5%).
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 Uses
1. It is used as a potent narcotic analgesic.
2. It is usually given in severe pains and also in such instances where patient
fails to show positive response to other analgesics.
3. It is found to sedate the respiratory centre, emetic centre and the cough centre
through its action in the medulla.
4. It stimulates the chemoreceptor-trigger-zone located in the medulla that
ultimately causes nausea and vomilting; and this is perhaps regarded as a side-
effect.
5. It also exerts sedative and hypnotic actions.
Note: Morphine and its salts are habit forming drugs. Hence, its use must be
done under the strict observation of a physician.

Codeine is the phenolic methyl ether of morphine and is widely used as an over-
the-counter analgesic and a cough suppressant. It is formulated with other
analgesic agents such as aspirin and paracetamol. Both morphine and codeine are
the most important analgesics for the management of moderate to severe pain.

Preparation It is invariably present in opium from 0.7 to 2.5% depending on the

sources of plant substances. However, mostly it is prepared by carrying out the
methylation of morphine

Uses
1. It is mostly used as a narcotic analgesic.
2. It is invariably employed as an antitussive.

A number of semisynthetic morphinanes have been produced as analgesics and

cough suppressants; these include pholcodine and dihydrocodeine. Morphine was
also used as a template for other analgesic agents including pethidine, which is one
of the most widely used synthetic opiates. Thebaine is the starting point for the
synthesis of many agents, including codeine and veterinary sedatives such as
etorphine.
Papaverine is an antispasmodic and is formulated with some analgesics such as
aspirin. It is also used as a treatment for male impotence, and its activity as a Ca2þ
channel blocker led to the development of verapamil. Apomorphine is prepared
by heating morphine with concentrated hydrochloric acid and has recently been

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shown to be of use in the treatment of Parkinson’s disease as this compound is a
dopamimetic.

tubocurarine, so named because the curare poison was carried in bamboo ‘tubes’
prior to use .Tubocurarine is a quaternary salt and as a chloride has found use as a
muscle relaxant in surgical procedures. The compound was also a template for the
development of other muscle relaxants of which atracurium (Tracrium) is an
excellent example.

Ipecac (Caephaelis ipecacuanha, Rubiaceae) is a shrub indigenous to Brazil and

produces rhizomes (underground stems) that were used by the indigenous peoples
to treat diarrhoea. The main alkaloidal components of this species are emetine,
psychotrine and cephaeline. Ipecac was used to treat amoebic dysentery, but the
side effects (vomiting, nausea and severe gastrointestinal disturbance) stopped its
use. However, it is used as an emetic in the form of a syrup to induce vomiting
after poisoning and drug overdose. In addition to its emetic and amoebicidal
properties, emetine is an expectorant and is added to many cough medicine

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