2. Plant derived therapeutic agents?
• Chemical constituents obtained from plant origin and used
therapeutically are termed as plant derived therapeutic
agents.
• The plant kingdom is comprised of 300,000-400,000
species.
• According to an estimate, only 5-15% of terrestrial plant
species have been investigated pharmacologically.
• About 25% of all medicines today have plant origins.
3. Quinine
• It is antimalarial drug, was obtained from the bark of Cinchona
species.
• It got approved by FDA in 2004.
• In 1820, two scientists, Pelletier and Caventou, isolated an
alkaloidal chemical in the cinchona bark which provided the
highest antimalarial effect and named it quinine.
• Cinchona bark contains about 30 alkaloids but its antimalarial
activity is mainly due to
i. Quinine
ii. Quinidine
iii. Cinchonine
iv. cinchonidine
4. Actions and uses
• It is a drug of choice for numerous ailments including
malaria, dyspepsia, fever, mouth and throat diseases and
cancer.
• Its actions are antipyretic, analgesic, anti-inflammatory
and antimalarial.
7. Biosynthetic pathway of quinine
Evident from the work of Moerloose, quinine and other alkaloids
are biosynthesized in young seedlings of cinchona species. Its
synthesis comprised of following steps:
a. Tryptophan condenses with 9 carbon trialdehyde (1) and
forms tetrahydro-β-carboline derivative (2).
b. Cleavage of β-carboline ring yields cinchonamine (3) which is
a minor alkaloid in chinchona bark.
c. Evident from a recent study, an indole alkaloid named
cinchophyllamine (5) is formed from cinchonamine which is
only isolated from leaves of C.ledgeriana.
d. Electrophillic attack of OH group at the β position of indole
nucleus of cinchonamine produces 3-hydroxyindolenine
derivative (4) which upon cyclization produces quinamine (6),
another minor alkaloid in cinchona plants.
8. e. Hydrolysis of C==N bond and oxidation of primary alcohol group of
compound 4 yields an intermediate compound (7) whose
cyclization yields another intermediate compound (8).
f. Dehydration of compound 8 produces the quinoline nucleus of
compound (9).
g. Reduction of the ketone group in compound 10 produces
cinchonidine (11) and cinchonine (13) which are epimers of each
other.
h. Whereas both reduction and methyoxylation of compound 10
produces quinine (10) and quinidine (12) which are epimers of each
other.
9.
10. Isolation & Extraction
1) The cinchona bark is stripped off and dried in the sun.
This is then crushed to a fine powder.
2) This dry powder is well mixed with 30% of its weight
with calcium hydroxide or calcium oxide and sufficient
quantity of sodium hydroxide to make a paste. It is
allowed to stand for few hours.
3) This mass is then transferred to Soxhlet apparatus and
extraction is carried out with benzene.
4) Subsequently benzene extract is shaken with
successive portions of 5% sulphuric acid.
5) The aqueous acid extract is adjusted to pH 6.5 with
dilute sodium hydroxide and cool. Crystals of neutral
quinine sulphate are formed.
11. 6) These crystals are freed from cinchonine and
cinchonidine by repeated recrystallization from hot
water.
7) Quinine sulphate crystals are dissolved in dilute
sulphuric acid and made alkaline with ammonia. Initially
amorphous quinine is formed, which becomes
crystalline.
8) Finally washed to remove sodium and ammonium salts
and dried to 45-55 ̊C.