Bitter principles lec.1 (2017)

Bitter Principles
Lecture-1
By
Dr. Ahmed Metwaly

Objectives:
I. Introduction
1. Definition
2. General characters
3. Classification
II. Terpenoid bitters
• Sesquiterpene Lactones
I. (−)-α-Santonin
II. Picrotoxin
III. Artemisinin
IV. Elephantopin
• Diterpenes
I. Forskolin

• Triterpenes
I. Quassin
II. Limonin

INTRODUCTION
Definition:
The bitter principles are heterogeneous compounds that doesn’t
belong to the class of alkaloids, but they have a characteristic
bitter taste.
General Characters:
•The term Bitters or Bitter principles is usually used to indicate
a group of natural products that have an intensely bitter taste
and were traditionally used in liquid medicaments to stimulate
appetite.
•Many of these products and drugs containing them are still
included in tonic formulations and are usually administered
before meals.

Bitter principles are mainly of vegetative origin, rarely of
animal origin and essentially comprise of C, H, and O, but
are rarely have or free from N.
•They are abundant in certain plant families especially
Compositae, Labiatae, Gentianaceae and Umbellifereae.
•Extracts of the following drugs have been used as bitter
stomachic: gentian, quassia, calumba, cinchona (or
quinine), nux vomica (or strychnine), hops, centaury,
condurago, quebracho and Taraxacum. Many of these drugs
are now mainly used for other pharmacological activities.

Classification
Two major classes of bitters could be distinguished: the
terpenoid or isoprenoid bitters and the non-terpenoid bitters.
I.Terpenoid bitters
This group includes isoprenoid bitters of different structures
such as:
1.Monoterpenoids (C10) e.g. iridoids (aucubin), secoiridoids
(gentopicrin); mostly in glycosidic forms.
2.Sesquiterpenoids (C15) containing a lactone ring and
subclassified to different groups.
3.Diterpenoids (C20) having labdane, kaurane and pimarane
structures e.g. marrubiin.
4.Triterpenoids (C30) e.g. cucurbitacins and quassinoids and

Monoterpenoid two isoprene units (C10H16)
Sesquiterpenoids three isoprene units (C15H24)
Diterpenoids four isoprene units (C20H32)
Sesterpenes five isoprene units (C25H40)
Triterpenoids six isoprene units (C30H48)
Tetraterpenoids eight isoprene units (C40H64)

II. Non terpenoid bitters
Compounds of this group are classified according to their
chemical structure into:
1.Phenolic bitters e.g. humulone and lupulone.
2.Chromone bitters e.g. khellin and visnagin.
3.Coumarin bitters e.g. xanthotoxin, imperatorin and bergapten.
4.Coumarone bitters e.g. rotenone.
5.Anhydride bitters e.g. cantharidin.
O O
O
-Pyrone-Pyrone
O O
O
ChromoneCoumarin
OO

Terpenoid Bitters
(−)-α-Santonin
They are C-15 lactone derivatives derived from farnesyl
pyrophosphate. The latter is a condensation product of three
isoprene units.

OH
O
CH3
COOH C
CH3
O
O
CH3
-SantoninSantonic acid
O

Biological Sources: It is
obtained from the dried
unexpanded flower heads of
Artemisia cina (Wormseed);
(family: Compositae).
Artemisia cina

Chemical name:1, 2, 3, 4, 4α, 7-Hexahydro-1-hydroxy-α, 4α-8-
trimethyl-7-oxo-2-naphthaleneacetic acid γ-lactone;
(C15H18O3).
Isolation:
•The powdered flower heads are treated with milk of lime [Ca
(OH)2] where upon the insoluble calcium santonicate is formed
and collected by filtration.
•On treatment with sodium carbonate or hydroxide the soluble
sodium santoninate is formed.
•Ca (OH)2 released from the reaction is precipitated as carbonate
by passing CO2. The suspension is filtrate.
•The filtrate (Na santoninate) is treated with sulfuric acid to
precipitate the crude santonin that is purified by recrystallization.
1.Santonin + Ca (OH)2  Ca santoninate
2.Ca santoninate + NaOH  Na santoninate
3.Na santoninate +H2SO4santonin.

Characteristic Features The three different forms of santonin
have the following characteristic features:
(a) (–)-Form of Santonin:
1. It may be obtained either as tabular crystals or as sphenoidal
crystals having mp170-173°C.
2. It is found to be practically tasteless with a positive bitter after taste.
3. Its specific optical rotation [α]D 25 ranges between – 170° to 175° (
in ethanol).
4. It turns yellow on being exposed to light.
5. It causes irritation to the mucous membranes.
(b) (+)-Form of Santonin:
1. It is obtained as colourless plates from methanol having mp 172°C.
2. Its specific optical rotation [α]D 20 + 165.9° (in ethanol).
(c) (±)-Form of Santonin:
1. It is obtained as colourless plates from methanol having mp 181°C.
2. It has uvmax (ethanol): 241 nm (log ε 4.10).

Uses:
1. It is mostly used as an anthelmintic (Nematodes).
2. It is very efficient in its action on round worms (e.g.
Ascaris) in doses of 60 to 200 mg daily for 3 days; but shows
less effect on the thread worms and none on taenia.
3. Due to its toxicity it is now replaced by other anthelmintics.

Toxicity:
•Santonin affects vision causing "xanthopsia" (white objects
look green, blue or yellow).
•It may also cause headache, vertigo, nausea, vomiting, apathy,
sweating and diarrhea.
•Large doses may give rise to epileptic convulsions followed
by coma, hearing disorders and heamaturia. Death may occur
from respiratory failure.

•It is generally used in combination with kainic (Digenic) acid
to reduce its toxicity. A mixture of the two drugs was found
more effective in the treatment of ascariasis than if each was
used separately.
kainic (Digenic) acid

Chromosantonin (Photosantonin): Santonin is fairly stable
in air, however, it turns yellow on
•Exposure to light whereby it gets converted into its isomeric
form chromosantonin, also known as photosantonin. The latter
may be rated into santonin by simply crystallisation from
Ethanol
“Photosantonin is inactive” that is why we use unexpanded
santonica flower heads

• Picrotoxin (Cocculin) O
O
O C
O
O
OH
H3C CH2
O
O
O C
O
O
OH
H3C CH3
OH
Picrotoxinin Picrotin
H
C15H16O6 C15H18O7
CH3
H
CH3

Biological Sources:
Obtained from the seed of
the fish berries Anamirta
cocculus L.
(Menispermaceae).
•Picrotoxin is isolated from
the endosperm of the seeds
as a bitter, crystalline, highly
toxic substance in an
amount attaining 1.5 %.
The name "picrotoxin" is a combination of the Greek words
"picros" (bitter) and "toxicon" (poison)

Chemical structure:
•Picrotoxin consists of equimolecular proportions of two
components: picrotoxinin and picrotin.
•These are readily separated on boiling picrotoxin with 20 parts
of benzene or CHCl3. Picrotoxinin is soluble in benzene,
while picrotin is precipitated.
•Both picrotoxinin and picrotin are highly oxygenated
sesquiterpenoid derivatives.
•Picrotin is non-toxic while picrotoxinin is toxic.
Chemical name: (1R,3R,5S,8S,13R,14S)-1-hydroxy-14-(2-hydroxypropan-2-yl)-13-methyl-4,7,10-
trioxapentacyclo [6.4.1.1⁹,¹².0³,⁵.0⁵,¹³]tetradecane-6,11-dione; (1R,5S,8S,13R,14R)-1-hydroxy-13-methyl-
14-(prop-1-en-2-yl)-4,7,10-trioxapentacyclo[6.4.1.1⁹,¹².0³,⁵.0⁵,¹³]tetradecane-6,11-dione

Isolation
•The powdered fruits are defatted with petroleum ether,
extracted, by boiling with alcohol or H2O and filtered.
•The filtrate is treated with lead acetate solution, then filtered
and the excess of lead acetate is removed as PbS by passing H2S
gas followed by filtration.
•The filtrate is concentrated to syrupy consistency and left in a
refrigerator, where upon picrotoxin is crystallized.
•Crude picrotoxin is purified by treatment with active charcoal
and re-crystallized from boiling water or alcohol.
•powdered fruits are defatted with petroleum ether
•+Alcohol Extract
•+ Lead acetate
•+ H2S gas
•Crystallization

1.It is obtained as shiny rhomboid leaflets mp 203°C.
2. It has an intense bitter taste and is extremely poisonous.
3. It has specific optical rotation [α]16 D – 29.3° (C = 4 in
absolute ethanol).
4. Solubility Profile: 1 g dissolves in 150 ml cold water; 45 ml
boiling water, in 13.5 ml 95% ethanol, in 3 ml boiling ethanol;
sparingly soluble in ether, chloroform; and readily soluble in
aqueous solution of NaOH and in strong NH4OH.
5. It is highly toxic to fish.
6. It is stable in air, but is affected by light.
7. Picrotoxin is almost neutral
Characteristic Features:

Uses
•Picrotoxin used by intravenous injection as antidote in
poisoning with barbiturates and other narcotics.
•It acts as CNS and respiratory stimulant (analeptic).
•Picrotoxin is highly toxic to fish, very small amounts of the
powdered fruits are sufficient to stupefy the animals.

Mechanism of action:
competitive-nonacts as aIthas a strong physiological action.It
chloride channels. It isreceptorAGABAfor thechannel blocker
therefore a channel rather than receptor antagonist
As GABA tself is an inhibitory neurotransmitter, infusion of
picrotoxin has stimulant and convulsant effects. As such,
picrotoxin can be used to counter barbiturate poisoning, that
can occur during general anesthesia or during a large intake
outside of the hospital.

Picrotoxin antagonizes the GABAA receptor channel directly,
which is a ligand-gated ion channel concerned chiefly with the
passing of chloride ions across the cell membrane. Therefore
picrotoxin prevents Cl- channel permeability and thus promtes
an inhibitory influence on the target neuron. Picrotoxin
reduces conductance through the channel by reducing not only
the opening frequency but also the mean open time. Picrotoxin
also antagonizes GABAC receptors (also called GABAA-rho
receptors) but the result of this action is not known. The
GABAC receptor is also linked to chloride channels, with
distinct physiological and pharmacological properties. In
contrast to the fast and transient responses elicited from
GABAA receptors, GABAC receptors mediate slow and
sustained responses.

Toxicity:
Oral, mouse: LD50 = 15 mg/kg. In large doses it is a powerful
poison, causing unconsciousness, delirium, convulsions,
gastro-enteritis and stimulation of the respiratory centre
followed by paralysis, from which death sometimes results.

Tests for identification
•Add few drops of H2SO4 to few crystals of picrotoxin, a
golden yellow color is developed that gradually changes to
reddish-brown.
•Sprinkle few crystals of picrotoxin onto a mixture of 4 drops of
H2SO4 containing about 0.2 gm KNO3 in an evaporating dish,
add NaOH solution drop wisely, the particles of picrotoxin
acquire a red color, which gradually fades.
•Moisten few crystals of picrotoxin with H2SO4, add one drop
of a solution of anisaldehyde in dehydrated alcohol (1:5). A
permanent blue color is developed.
• Picrotoxin gives a green color on boiling with vanillin
hydrochloride solution.
•Picrotoxin reduces Fehling’s and ammoniacal AgNO3
solutions.

Artemisinin
Structure;
A characteristic feature in the structure of artemisinin is the
presence of an endoperoxide moiety which is essential for the
antimalarial activity.
Chemical name;
(3R,5aS,6R,8aS,9R,12S,12aR)-Octahydro-3,6,9-trimethyl-3,12-epoxy-
12H-pyrano[4,3-j]-1,2-benzodioxepin-10(3H)-one

Biological Source;
It is obtained from the
leaves and the closed,
unexpanded flower heads of
Artemisia annuna Linn.,
family Asteraceae.
Artemisia annuna
This particular herb has been used in the Chinese system of
medicine exclusively for the treatment of malaria since more
than one thousand years.
A characteristic feature in the structure of artemisinin is the
presence of an endoperoxide, artemisinin was isolated and
identified in 1972.

To date, Artemisinin and its simple derivatives have been
tested in China to treat more than 1.5 million, patients
suffering from malaria and particularly cerebral malaria; and it
has been shown to be valuable and effective against resistant
strains of Plasmodium

Uses;
• Artemisinin is an excellent antimalarial, approximately
equal in potency to chloroquine. There are two reasons for
the great interest being shown in artemisinin and its
derivatives.
a- Active against chloroquine resistant strains of Plasmodium
falciparum.
b- The high lipid solubility ensures rapid penetration into CNS;
so it’s a first-line drug for the treatment of cerebral malaria
caused by P. falciparun, which is otherwise fatal.
Dosing;
Artemisinin and derivatives have half-lives on the
order of an hour. Therefore, they require at least
daily dosing over several days. For example, the
WHO-approved adult dose of co-artemether is
four tablets at 0, 8, 24, 36, 48, and 60 hours (six
doses)

Mechanis of Action;
The drug has a high affinity for hemozoin, a storage form of
haem which is retained by the parasite after digestion of
hemoglobin, leading to a highly selective accumulation of the
drug in the parasite. Artemisinin then decomposes in the
presence of iron, probably from hemozoin and releases free
radicals (hydrogen peroxide) which kill the parasite. The
peroxide bridge is therefore a crucial part of the drug molecule as
was suspected from structure activity studies

Modifications in Structure;
On account of the poor water solubility of artemisinin an
attempt was made to improve either its water solubility ir its
lipid solubility. In the former instance, Sodium artesunate i.e.,
the sodium salt of its hemisuccinate ester was developed; while
in the latter instance,
Artemether i.e., its corresponding methyl ether analogue was
produced. Evidently, sodium artesunate is employed for
intraveneous injections and artemether is used as a potent long
acting drug.

The WHO has recommended artemisinin combination
therapies (ACT) be the first-line therapy for P. falciparum
malaria worldwide. Combinations are effective because the
artemisinin component kills the majority of parasites at the
start of the treatment, while the more slowly eliminated
partner drug clears the remaining parasites.
Several fixed-dose ACTs are now available containing an
artemisinin component and a partner drug which has a long
half-life, such as mefloquine (ASMQ), lumefantrine
(Coartem), amodiaquine (ASAQ), piperaquine (Duo-
Cotecxin), and pyronaridine (Pyramax).

Elephantopin
Structure;
Elephantopin is a sesquiterpene lactone containing two lactone
rings and an epoxide function.
Chemical name;
(1aR,8S,8aR,11aS,11bR)-1a-Methyl-9-methylene-5,10-dioxo-
2,3,5,7,8,8a,9,10,11a,11b-decahydro-1aH-3,6-(metheno)furo[2,3-
f]oxireno[2,3-d][1]oxacycloundecin-8-yl methacrylate

Biological source;
Elephantopin is obtained from Elephantopus elatus,
Family Compositae
Elephantopus elatus

Uses:
Elephantopin has been shown to have an antitumour activity.

Forskolin (Coleonol)
Forskolin is a recently discovered labdane diterpene that
originates from the Ayruvidic system of medicine.
(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-6,10,10b-trihydroxy-3,4a,7,7,10a-
pentamethyl-1-oxo-3-vinyldodecahydro-1H-benzo[f]chromen-5-yl acetate

Biological source;
from the Indian Coleus plant (Coleus forskohlii)
Coleus forskohlii

Uses;
• Forskolin has been demonstrated to have hypotensive,
cardiotonic and platelet aggregation inhibitory activity;
because of its adenylate cyclase stimulant activity, it is
considered a promising drug for the treatment of glaucoma,
congestive cardiopathy and asthma.
• Forskolin is now being marketed in Japan (hypotensive and
spasmolytic).
• Forskolin activates the enzyme adenylyl cyclase and
increases intracellular levels of cAMP. cAMP is an
important second messenger necessary for the proper
biological response of cells to hormones and other
extracellular signals.

Quassin
Chemical name: (3aS,6aR,7aS,8S,11aS,11bS,11cS) -1,3a,4,5,6a,7,7a,8,11,
11a,11b,11c-dodecahydro-2,10-dimethoxy-3,8,11a,11c- tetramethyldibenzo[de,g]
chromene-1,5,11-trione
Structure ;
Quassin is an intensely bitter oxygenated triterpenoid
characterized by having a lactone structure. Quassin and related
compounds constitute the group of quassinoids or amaroids

Biological source:
Quassin is the main constituent
of quassia wood, which is the
stem wood of Picrasma excelsa
known in commerce as Jamaica
quassia or of Quassia amara
known in commerce as Surinam
Quassia family Simarubaceae .
Quassia amara

Isolation;
• The aqueous decoction of t wood is concentrated and
neutralized with Na2CO3.
• Tannic acid solution is added gradually, until no more
precipitate is formed.
• The precipitate is collected, triturated with lead carbonate
(to form lead tannate and liberate quassin) then dried on a
water bath.
• The produced mass is powdered and repeatedly extracted
with alcohol 80 %.
• The combined alcoholic extracts are concentrated and left
to allow crystallization of quassin.

Characteristic Features;
Quassin is obtained as rectangular plates from dilute methanol
having mp 222°C.
2. Its specific optical rotation [α]20 D + 34.5° (C = 5.0 g in
CHCl3).
3. It has uvmax: ~ 255 nm (ε ~ 11,650).
4. It is extremely bitter; and it has the bitterness threshold 1 :
60,000.
5. It is found to be freely soluble in benzene, acetone, ethanol,
chloroform, pyridine, acetic acid, hot ethyl acetate; and
sparingly soluble in ether and petroleum ether.

Test for Identification;
• Add concentrated H2SO4 and sucrose to few crystals of
quassin, a red color is produced.
• An alcoholic solution of quassin gives crimson color with
phloroglucin and HCl.

Uses;
• Quassia wood extract is used as a bitter tonic.
• The drug has anthelmintic properties, and is administered as
enema for expulsion of threadworms.
• It also used as insecticide.

Limonin
Structure;
Limonin is a modified triterpenid compound belonging to
the class of limonoids with or derived from a 4,4,8-trimethyl-17-
furanylsteroid skeleton.
Limonoids constitute a group of secondary metabolites
which are commonly found in the order Rutales mostly in family
Meliaceae and less frequently in the Rutaceae

Biological source;
• Limonin is isolated from the pericarp of Citrus limonis and
other Citrus species (Rutaceae).
• It occurs in the fruits and its juice as a non-bitter monolactone
precursor which undergoes further lactonisation with
formation of a second lactone ring to yield limonin
Citrus limonis

Uses;
• Limonoids act as insecticides, insect growth regulators and
insect antifeedants.
• They have antibacterial, antifungal and antiviral properties.
• They have possible anticarcinogenic activity.

Summary:
I. Introduction
1. Definition
2. General characters
3. Classification
II. Terpenoid bitters
I. (−)-α-Santonin
II. Picrotoxin
III. Artemisinin
IV. Elephantopin
• Diterpenes
I. Forskolin

Bitter principles lec.1 (2017)

More Related Content

What's hot (20)

Viewers also liked (20)

Similar to Bitter principles lec.1 (2017) (20)

More from Ahmed Metwaly (20)

Recently uploaded (20)

Bitter principles lec.1 (2017)