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Bitter Principles Lecture-1 By Dr. Ahmed Metwaly
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  • Bitter Principles

    Lecture-1

    By

    Dr. Ahmed Metwaly

  • Objectives: I. Introduction

    1. Definition

    2. General characters

    3. Classification

    II. Terpenoid bitters

    Sesquiterpene Lactones

    I. ()--Santonin

    II. Picrotoxin

    III. Artemisinin

    IV. Elephantopin

    Diterpenes

    I. Forskolin

  • Triterpenes

    I. Quassin

    II. Limonin

  • INTRODUCTION

    Definition:

    The bitter principles are heterogeneous compounds that doesnt

    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

    Sesquiterpene Lactones

    ()--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 acidO

  • 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, 4, 7-Hexahydro-1-hydroxy-, 4-8-

    trimethyl-7-oxo-2-naphthaleneacetic acid -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 +H2SO4santonin.

  • Proposed Biosynthesis:

  • 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 mp170-173C.

    2. It is found to be practically tasteless with a positive bitter after taste.

    3. Its specific optical rotation []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 172C.

    2. Its specific optical rotation []D 20 + 165.9 (in ethanol).

    (c) ()-Form of Santonin:

    1. It is obtained as colourless plates from methanol having mp 181C.

    2. It has uvmax (ethanol): 241 nm (log 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

  • Test for identification:

  • 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 [6.4.1.1,.0,.0,]tetradecane-6,11-dione; (1R,5S,8S,13R,14R)-1-hydroxy-13-methyl-14-(prop-1-en-2-yl)-4,7,10-trioxapentacyclo[6.4.1.1,.0,.0,]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 203C.

    2. It has an intense bitter taste and is extremely poisonous.

    3. It has specific optical rotation []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 -non acts as aIt has a strong physiological action. It

    chloride channels. It is receptor AGABA for the channel 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.

    https://en.wikipedia.org/wiki/Channel_blockerhttps://en.wikipedia.org/wiki/Channel_blockerhttps://en.wikipedia.org/wiki/Channel_blockerhttps://en.wikipedia.org/wiki/GABAA_receptorhttps://en.wikipedia.org/wiki/GABAA_receptorhttps://en.wikipedia.org/wiki/GABAA_receptorhttps://en.wikipedia.org/wiki/GABAA_receptorhttps://en.wikipedia.org/wiki/Channel_blockerhttps://en.wikipedia.org/wiki/Barbiturate

  • 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 Fehlings 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

  • Biosynthesis in A. annua

  • 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 its 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 222C.

    2. Its specific optical rotation []20 D + 34.5 (C = 5.0 g in

    CHCl3).

    3. It has uvmax: ~ 255 nm ( ~ 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

    Sesquiterpene Lactones

    I. ()--Santonin

    II. Picrotoxin

    III. Artemisinin

    IV. Elephantopin

    Diterpenes

    I. Forskolin

  • Triterpenes

    I. Quassin

    II. Limonin