Pharmacognosy -2 PHG 322 - Psau€¦ · 3-Isoquinoline alkaloids Isoquinoline Alkaloids: - More than 800 alkaloids belong to this group. - They have been derived from isoquinoline,

Prof. Dr. Amani S. Awaad

Professor of PharmacognosyPharmacognosy Department,

College of Pharmacy Salman Bin Abdulaziz

University,

Al-Kharj. KSA.

Email: [email protected]

Pharmacognosy -2

PHG 322

What are Isoquinoline alkaloids

*types , uses, physical & chemical properties of

Isoquinoline alkloids

What are Quinoline alkalaloids

types , uses, physical & chemical properties of

Quinoline alkalaloi

Typical/hetrocyclic alkaloids

3-Isoquinoline alkaloids

3-Isoquinoline alkaloidsIsoquinoline Alkaloids:

- More than 800 alkaloids belong to this group.

- They have been derived from isoquinoline, 1,2,3,4-tetrahydro- or 3,4 -dihydro-derivatives.

- It is important to take in consideration that the basic nucleus (Isochinoline) could be opened or enlarged.

- Nine types of isoquinoline alkaloids have pharmacognostical interest such as:

1. Benzylisoquinoline type (e.g. papaverine)

2. Bisbenzylisoquinoline type (e.g. tubocurarine)

3. Phthalidisoquinoline type (e.g. Noscapine, Hydrastine)

4. Protoberberine type (e.g. berberine)

5. Aporphine type (e.g. boldine)

6. Protopine type (e.g. protopine)

7. Morphinane type (e.g. morphine, codeine, thebaine)

8. Benzophenanthridine (e.g. chelidonine, sanguinarine)

9. Emetine- (Monoterpenoid isoquinoline) type (e.g. emetine)


The basic biosynthetic reactions of these compounds result from the Mannich-condensation of

Phenylethylamine with keto derivatives.

The Phenylethylamine is obtained from phenylalanine or tyrosine or 3,4-dihydroxy L-phenylalanin after decarboxylation.

The carbonyl derivative could be aliphatic

aldehyde or alpha-keto acid

The lead to :-formation of simple tetrahydro-isoquinoline alkaloids

- iridoid (biosynthesis of monoterpenoid- isoquinolinealkaloids

- emetine type) or phenylacetaldehyde derivative (biosynthesis of benzylisoquinoline alkaloids.

- The bisbenzylisoquinoline molecules

- The important drugs which contain such alkaloid

of this group are: Opium, Ipecac, Hydrastis,

Curare, and Berberis.

*Isoquinoline alkaloids are widespread in the following

plant families, Aristolochiaceae, Magnoliaceae,

Lauraceae, Menspermaceae, Ranunculaceae,

Papaveraceae (Papaver, Argemone, Chelidonium) and

Fumaraceae.


Opium (Crude)

It is the air-dried milky exudates obtained by incising the unripe capsules of

Papaver somniferum (Papaveraceae).

- The opium is an annual herb about 50-150 cm in height, with large showy

solitary flowers varying in color from white to pink or purple.

- The drug contains organic acids especially meconic acid (dicarboxylic pyrone)

about 5%. The active principles are represented by 10 to 20% alkaloids

alkaloids of different types have been obtained from opium and its extracts.

- The most important type is the morphinane type.

- The most important alkaloids of this group are morphine (5-25%), codeine

(0.2-3%), Thebaine (0.2-5%), oripavine, and salutaridine.

Other alkaloids are derived mainly from;

- benzylisoquinoline (papaverin, reticuline),

- phthalidisoquinoline type (narcotine, narceine) and

- protopine type (protopine, cryptopin). morphinane type

3-Isoquinoline alkaloidsOpium (Crude)

1-Morphine

is the major alkaloid of morphinan group. It is the pentacyclic molecule with five asymmetric centers: only the naturally occurring enantiomer (Levorotatory, 5R, 6S, 9R, 13S, and 14R) is active.

- The presence of a phenolic hydroxyl group at (C-3) gives this specific solubility.

- Solubility in hydroxides is due to the formation of morphinates.

- The phenolic function is responsible for the reducing characters of the molecule, which can be characterized in the presence of ferric salts.

- The phenolic OH-group at C-3 and the hydroxyl group at C-6 can be etherified or esterified: besides the naturally-occurring derivatives like codeine or thebaine.


1-Morphine

Introduction of a hydroxyl

group at C-14 increases the

analgesic activity.

Esterifications or etherification

of the hydroxyl group at C-3

decreases the analgesic activity.

The inversion of the

configuration at C-9 and

C-13 makes the activity

disappear.

Substituents on the N-atom are crucial; the

replacement of the methyl group by small alkyl

radicals (e.g. allyl, cyclopropylmethyl,

cyclobutylmethyl) transforms the compound

into a partial or a complete opioid antagonist

Structure-activity relationship of morphine:


1-Morphine

Pharmacological Activity

- It is pure agonist, which acts by mimicking the activity of endorphins on the pre-synaptic receptors of

myelinated fibers. the result are an inhibition of the release of substance P, which is pain

neurotransmitter.

- Morphine inhibits the production of enkaphalins and the number of receptors increase as a result, hence

the tolerance during withdrawal, the receptors can not be saturated by their natural ligands, and the

withdrawal syndrome results as the clinical manifestation of the physical dependence

Morphine depresses the respiratory centers in the brain stem. The speed of onset of this depression is afunction of the route of administration: very fast (5-7 minutes) by IV injection, maximal by intrathecalinjection (12-24 hours).

- Morphine depresses the cough center. It causes myosis. Morphine acts on the pituitary to decrease thesecretion of FSH, LH and ACTH

- Morphine can be used as starting material for the synthesis of apomorhine (as emetic drug used), and ofnalorphins (morphine antagonist, antidote by atemdepression caused by morphine).


2-Codeine

is the most widely used opium alkaloid.

- It may be obtain from opium or by methylation of morphine or from thebaine by reduction and demethylation.

- Codeine is methyl morphine in which the methyl group replaces the hydrogen of the phenolic OH-group.

- Codeine and its salt occur as fine needles or as white crystalline powders.

Pharmacological Activity : Codeine has antitussive activity. This activity is accompanied by a slight depression of therespiratory centers, a slight broncho-constriction due to a direct effect on smooth muscles, a decrease in secretions, and arelease of histamine.

- Codeine is also a potent analgesic, acting like morphine on enkephalinergic receptors, but with a much less intense action.An efficacious analgesic (30-60 mg), its effect is cumulative with those of painkillers such acetylsalicylic acid orparacetamol.


3-Papaverine

Papaverine is an alkaloid found in opium but not closely related to

the other opium alkaloids in its structure or pharmacological actions

1-It is devoid of CNS-effects, a musculotropic spasmolytic which relaxes smooth muscle fibers especially those of cerebral, pulmonary, and systemic peripheral blood vessels, but also those of bronchia, intestines, ureter and biliary ducts.

2-It has an effect on the heart muscle and increases coronary blood flow. Its activity is due to its ability to inhibit the phosphodiesterase, which hydrolyzes cAMP, andto decrease the intracellular calcium concentration.

3-It is used alone as a sustained-release oral form, at a dose of 250 to 350 mg/day. Its current indications are psychological and behavioral problems of senility (loss of attention and concentration).

4-It is also used to treat the CVA (cerebrovascular accidents), the symptoms of ischemia in the eye, and symptoms of arteritis in the lower legs.

Pharmacological activities and use

It conceder to be one of Benzylisoquinoline type


4-Noscapine

It is not derived from morphinan and is devoid of addicting effects. It is not an

analgesic, nor does it induce respiratory depression. It is a specific antitussive

through its central and peripheral activities.

Its one of Phthalidisoquinoline type


Tests for opium :

Tests due to phenolic properties: 1- Morphine gives a blue color with FeCl3.

2- Nitrous acid test: solution of morphinein dilute HCl + NaN02 +NaOH( red color).

3- Morphine + dil H2SO4 + HI→ I2give violet colour when dissolve in CHCl3

Tests with alkaloidal color reagents: 1- Liebermann' s reagent (black color).

2- Mandalin's reagent (bluish-gray color).

3- Marquis' reagent (violet color).

4- HNO3→red colour convert to yellow on heating

4- Codeine + concentrated H2SO4+ FeCl3, warm in water bath (bluish violet color + HNO3 Red color

The identity of opium can be confirmed by directly adding ferric chloride to

the aqueous extract ( red color develops) characteristic of meconic acid.

TLC analysis characterizes the principal alkaloids contained in a 70% ethanol

extract , sprayed by Dragendrof reagents-iodobismuthate


Opium is both a blessing and a curse,

depending on who processes it.

HPTLC is the only technique capable

of quantifying all the six important

alkaloids in opium from hundreds of

samples when the seasonal crop is

ready.

These alkaloids can be sensitively and

specifically detected by post

chromatogram derivatisation using

dragendorff reagent.

Detection in Forensic Science

H.W

Reed and comment ?


H.W

Reed and comment ?


Ipecac alkaloids

Ipecac yields about 2% of the ether soluble alkaloids of ipecac.

The active principles are isoquinoline alkaloids.

They contain in their molecules two tetrahydroisochioloine nucleus.

Ipecac consists of the dried rhizome and roots of Cephaelis

ipecacuanha (Fam. Rubiaceae) known in commerce as Rio or

Brazilian ipecac or of Cephaelis acuminata, known in

commerce as Cartagena.

Source

Contents


Ipecac alkaloids

- Emetine is the major constituent of Rio Ipecac (60-75%)

of the total alkaloids) but it forms only 30-50% of the

total alkaloids of Cartagena Ipecac.

- The other alkaloids possess similar chemical structures:

cephaline (monophenolic) and psychotrine.

- It is the fact that cephaline on methylation gives emetine

and psychotrine on reduction gives cephaline.

Alkaloids of Ipecac

NH

N

H3CO

H3COOCH3

OCH3

Emetine

NH

N

H3CO

HOOCH3

OCH3

Psychotrine

NH

N

H3CO

HOOCH3

OCH3

Cephaline

H2

Reduction

ReductionMethylation

Methylation


Ipecac alkaloids

Pharmacological activities and use

Ipecac preparation, when administered orally at low doses, is emetics.

- Cephaline is the main alkaloid responsible for the emetic activity,

where as emetine is mostly an expectorant.

- Emetine is an amebicides, inhibits protein synthesis in animals and

in protozoa. It kills viruses, but it is not antibacterial.

Emetine is toxic for humans.

- Arrhythmia, hypotension, muscular weakness, and gastrointestinal

distress are common side effects.

- It is no longer used in therapeutics. It has been replaced by synthetic

derivatives, dehydrometine, whose subacute and chronic toxicity are

decreased by lower accumulation.

- Dehydroemetine is used for treating acute intestinal amebiasis, hepatic

amebiasis and bilharziasis


• It is a crude dried extract from the bark and stems of Strychnos castelnaei, Strychnostoxifera, Strychnos crevauxii (Fam. Loganiaceae)

• and from Chondodendron species (Fam. Menispermaceae) used as arrow poison by certain native tribes of the Amazon regions of South America.

• The term curare is the phonetic transcription of the Caribbean word ourari, or woorarifor poison.

• The young bark is scraped off the plants, mixed with other substances and boiled in water and strained or extracted by crude percolation with water.

• It is evaporated to a paste over a fire or in the sun.

• The earliest available preparations were named according to the containers in which the drug was packaged.

Curare Alkaloids

Curare Alkaloids are group of isoquinoline alkaloids belonging to Bis-benzyltetrahydroisoquinolines type.

Source

http://www.google.com.sa/url?sa=i&rct=j&q=&esrc=s&frm=1&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjCntDmsrDJAhVEWhQKHTpYBksQjRwIBw&url=http://naturespoisons.com/tag/strychnos-toxifera/&psig=AFQjCNExnbDPi3xm5HInRdfyc0LAW3Xl7Q&ust=1448706602321368


Curare AlkaloidsSource

• Calabash (gourd) poured into the fruits of various Bignoniaceae, originally from Colombia, Venezuela and used as arrow poison, it contains extracts of trunk barks of various shrub of the genus Strychnos (Loganiaceae) including Strychnos toxifera and Strychnos letails etc.

• Tube (bamboo) curare from Brazil and Peru, poured into bamboo tubes and used as arrow poison. It is composed chiefly of extracts of stems of Menispermaceae of the genusChondrodendron tomentosum and of the very close genus Curarea (C. toxifera).

• Pot (clay pot) curare poured into clay pot of various shapes, rare and specific to the upper Orinoco and upper Amazon basins; it contains a mixture of extracts of Menispermaceaeand Loganiaceae.

• The active constituents of curares are very different according to the plant extract used.


Curare AlkaloidsA-Menispermaceous curares

contain from 2 to 10% bisbenzyltetrahydroisoquinoline alkaloids.

- The curare molecule is (+)-tubocurarine, which has asymmetrical quaternary ammonium structure with two ether bridge.

- The other alkaloids are tertiary bases: (-) curine, (-)-isochondrodendrine and(+) chondrocurine.

- Tubocurarinechloride or (+)-tubocurarine is a white or yellowish white to grayish white, odorless crystalline powder.

- It is derived from tube curare and was isolated in 1935. - It is soluble tis in water and in alcohol but insoluble in acetone , chloroform

and ether.

- it is a non-depolarizing neuromuscular blocking agent and was employed i.m. or i.v. as a skeletal muscle relaxation in surgical procedures.

- Its uses was discontinued about 10 years ago.

- A semisynthetic derivative of C-toxiferine is used N,N-diallylnortoxiferinium dichloride (=alcuronium), which is used i.v. as adjunct in anesthesia.

curine

isochondrodendrinechondrocurine.


Curare Alkaloidsb-Loganiaceouss curares

The active constituent are symmetrical bis quaternary

ammonium alkaloids,

C-toxiferine (calabash), C-curarine, C-alkaloid G and E, C-

calebassine and others (indole alkaloids)

The crude extract exhibits a paralyzing effect on voluntary

muscle (curariform effect) by blocking nerve impulses to

skeletal muscles at the myoneural junction.

It also produces a toxic action on blood vessels as well as

histamine-like effect.

C-toxiferine

3-Isoquinoline alkaloidsIsoquinoline Alkaloids:

- More than 800 alkaloids belong to this group.

- They have been derived from isoquinoline, 1,2,3,4-tetrahydro- or 3,4 -dihydro-derivatives.

- It is important to take in consideration that the basic nucleus (Isochinoline) could be opened or enlarged.

- Nine types of isoquinoline alkaloids have pharmacognostical interest such as:

1. Morphinane type (e.g. morphine, codeine, thebaine)

2. Benzylisoquinoline type (e.g. papaverine)

3. Phthalidisoquinoline type (e.g. Noscapine, Hydrastine)

4-Emetine- (Monoterpenoid isoquinoline) type (e.g. emetine)

5. Bisbenzylisoquinoline type (e.g. tubocurarine)

6. Protoberberine type (e.g. berberine)

5. Aporphine type (e.g. boldine)

6. Benzophenanthridine (e.g. chelidonine, sanguinarine)

7.Protopine type (e.g. protopine)


Drugs containing Protoberberines and related alkaloids

GOLDENSEAL

The drug consists of the dried rhizome and roots of Hydrastis Canadensis (Fam.:Ranunculaceae).

The rhizome has unpleasant odor and a bitter taste, show internally a golden yellow color.

The plant is perennial herb with a short horizontal rhizome that bears numerous long,slender roots; it grows wild in the eastern part of North America where it was formerly usedby the Cherokee peoples.

Hydrastis is Greek and means to accomplish or act with water, the species name refers tothe habitat.

Goldenseal was plentiful in the forests of the eastern U.S. and Canada.

The chief components of the drug are isoquinoline: hydrastine (a phthalytetrahydroisoquinoline)

and berberine, a bright yellow quaternary ammonium Protoberberines.

components

hydrastin


GOLDENSEAL

hydrastin

Berberine is a bacteriostatic at low doses and bactericide at higher doses.

In vitro, it is active against many germs (Staphylococcus, Streptococcus, but also Salmonella, Proteus, Vibrio) it is also fungicide and it is toxic for various protozoa (Leishmania, Plasmodium). It decreases intestinal peristalsis.

Hydrastine chloride is combined with chlorhexidine and synepherine in eye drops used to treat conjuctival hyperthermia of allergic or seasonal origin and eye strain due to environmental irritations.

Pharmaceutical preparation (tincture, extracts) are used in combination with other plants thought to be vascular protective agents (Whitch Hazel, Cypress, Black Haw)

Hydrastine and berberine are used as astringent in inflammation of mucous membrane.

These phytopharmaceuticals are used in the symptomatic treatment of venous and lymphatic vessel insufficiency

Uses


Drugs containing Protopine type and related alkaloids

FUMITORY

The plant Fumaria officinalis (Fam. Fumariaceae) and related species are perennial herbaceous plants with bluish green leaves. The drug consists of the flowering plant.

Constituents:

The principal alkaloid of Fumaria officinalis is protopine together with spiro-benzyltetrahydroisoquinoline (fumaricine, fumarofine) and protoberberine.

Uses:

The drug is amphochleretic it means it normalizes the biliary flow.

It is also a spasmolytic; protopine is a spasmolytic, anticholinergics, an antiarrhythmic and an antibacterial.

Phytopharmaceuticals based on fumitory are traditionally used to enhance renal and digestive elimination functions and as a choleretic and cholegogic

Typical/hetrocyclic alkaloids

4-Quinoline alkaloids


Cinchona consists of the dried bark of Cinchona pubescens(Cinchona succirubra) or of its varieties (Fam. Rubiaceae).

All cinchonas are indigenous to the eastern slopes of the Amazonian area of the Andes where they grow between 1500 and 3000 m.

Alkaloids containing Quinoline as their principle nucleus include those obtained from cinchona (quinine, quinidine, cinchonine and cinchonidine).

Cinchona

The alkaloids of Cinchona appear to be present in the

parenchymatous tissues of the bark, in combination with special

organic acids chiefly quinic acid and cinchotannic acid.


CinchonaConstituents

Quinine is a diacidic base forming two series of salts, the “basic” and the “neutral” salts.

It occurs as white, odorless, bitter crystals. The neutral salts are more soluble in water than the basic salts.

This difference in solubility between the two series of salts can be basis for the extraction and purification of quinine.

The basic salts in solution actually have a neutral reaction. Quinine is a distereoisomer of quinidin

On the other hand, the neutral salts in solution have an acidic reaction

The basic skeleton of these alkaloids is 9-rubanol, which is derived from the parent compound named ruban.

The ruban nucleus is given to the combined Quinoline ring system attached through a methylene group to a bicyclic ring system named quinuclidine.

The principal alkaloids are the stereosiomers, quinine and quinidine, and their 6΄-demethoxylated homologs cinchonine and cinchonidine


Cinchona

Cinchona and its alkaloids have been used in the treatment of malaria fever for many

years.

Overdoses of cinchona products results in temporary loss of hearing and in impaired

sight. Ringing in the ears is a symptom of toxicity (Cinchonism).

Quinine is antimalarial agent. It is more active on Plasmodium vivax than on

Plasmodium flaciparum.

It is schisonticide, inactive on the sporozoites and the tissue stages, and virtually inactive

on the gametocytes.

It is believed to act by interaction of the Quinoline moiety into DNA of the Plasmodium

parasites, thereby reducing the effectiveness of DNA to act as a template.

Quinine is only modestly antipyretic and analgesic

Activities & uses


CinchonaActivities & uses

The current indications of quinine include the following:

1- It is used for treating of pernicious malaria and of cases resistant to 4-

aminoquinolines.

In case of acute attack, it is administered at a dose of 10 mg/kg by slow infusion, every

8 h. for treating malaria, which is resistant to multiple drugs and in the absence of acute

attack, the normal dose in adult 1.5-2 g/day in 3 or 4 doses for 10 to 14 days

2- The symptomatic treatment of fevers and aches as well as flu-like states.

3- Quinone ascorbate, combined with vitamins, used in the combination with thiamine, to relieve muscle cramps (orally and rectally)Quinidine (as gluconate, polygalacturonate, sulphate) is an antiarrhythmic described as class I (sodium channel blockage). It inhibits the rapid sodium influx; decrease the rate of depolaraization, contractility, and the atrial and intraventricular conduction velocity.It is used for treating various cardiac arrythmias such as premature atrial, ventricular contraction, atrial and ventricular tachycardia, and atrial flutter and atrial fibrillation


Cinchona

1- With oxygenated acids (e.g. sulphuric and acetic acid)

• Quinine and quinidine produce a strong blue fluorescence when dissolved in these acids.

2- Thalleioquin Reaction

• Quinine and quinidine is solution in dilute sulfuric acid can be treated by bromine until the fluorescence disappears. The addition of aqueous ammonia causes the development of an emerald green color, which can be extracted with chloroform.

3- The addition of potassium ferricyanide in alkaline medium leads to a purplish red color that can also be extracted with chloroform.

Tests:


Cinchona

• The trunk bark, root bark, and the fruit of this large tree indigenous to southern china and contain 0.01, 0.02 and 0.03% camptothecine, respectively.

• It is characterized by a pyrrol 3,4b] Quinoline sequence. It is a neutral lactam, which does not react with the general reagents for alkaloids and doesn’t form stable salts.

• Camptothecine exert cytotoxic and antitumor activity, but because of its toxicity, its synthetic analogs such as Topotecan and CPT11 have been used for treating some type of cancers.

• There was evidence that this compound has some activity in topoisomerase I (an enzyme involved in the uncoiling of DNA, a prerequisite for replication and transcription).

Camptotheca acuminata (Fam. Nyssaceae)

Documents

Pharmacognosy -2 PHG 322 - Psau€¦ · 3-Isoquinoline alkaloids Isoquinoline Alkaloids: - More than 800 alkaloids belong to this group. - They have been derived from isoquinoline,