Pharmacognosy | Alkaloids

Alkaloids

Physiologically active organic nitrogenous compounds with varied pharmacologic actions

Majority of plant activities

Due to alkaloids

Alkaloids — General properties

Basic pH, bitter taste; usually crystalline or amorphous

Alkaloids — Oxygen content and physical state

Most contain oxygen and are solid

Alkaloids — liquid alkaloids (4)

Coniine, nicotine, sparteine, arecoline

Alkaloids — General color

Generally white solid substances

Alkaloids — other colors

Berberine is yellow;
sanguinarine is colorless and yields red salts

Sanguinaria

Crude drug also known as blood root; used by Indians to color their faces

Sanguinarine color change

Colorless while still in the plant, but becomes red when cut and exposed to oxygen

Makabuhay

Rich in berberine; its extract turns brownish-yellow after extraction and evaporation

Primary amine alkaloid

Mescaline; RNH₂

Secondary amine alkaloid

Ephedrine; R₂NH

Tertiary amine alkaloid

Atropine; R₃N

Quaternary amine alkaloid

Tubocurarine

True alkaloid requirement

It should be derived from amino acids

L-tryptophan alkaloid — examples (2)

Strychnine, LSD

L-tyrosine alkaloid — examples (2)

Morphine, papaverine

Alkaloids — origins (6)

1. Lysine

2. Ornithine, Aspartate

3. Ornithine

4. Tryptophan

5. Tyrosine

6. Purine

Amino Acid source: Lysine

Alkaloid product: Coniine, Lobeline
Structure: Piperidine

Amino acid source: Ornithine & Aspartate

Alkaloid product: Nicotine
Structure: Pyridine, Pyrrolidine

Amino acid source: Aspartate

Alkaloid product: Cocaine, atropine, hyoscyamine, scopolamine
Structure: Tropane

Amino acid source: Tryptophan

Alkaloid product: Quinine
Structure: Quinoline

Amino acid source: Tyrosine

Alkaloid product: Morphine, berberine, hydrastine, emetine, sanguinarine, opium alkaloids
Structure: Isoquinoline

Amino acid source: Purine (Aspartate, Glycine, Glutamine)

Alkaloid product: Caffeine, theobromine, theophylline
Structure: Purine

Alkaloidal base — AKA

free alkaloids

Alkaloidal base — Solubility

Insoluble in water and soluble in organic solvents

Alkaloidal base — Organic solvents (2)

Ether, chloroform, and other non-polar solvents

Alkaloidal base — Remedy to make alkaloidal bases soluble in water

Convert them into salts

• salt form: freely soluble in water

• example: Quinine + H₂SO₄ = Quinine sulfate

Alkaloidal salts + inorganic base = ?

Alkaloidal base or free alkaloid

Alkaloidal base + inorganic acid = ?

Alkaloidal salt

Discovery — Derosne

Narcotine (1803)

Discovery — Serturner

Morphine (1816)

Discovery — Pelletier and Caventou (8)

Brucine, emetine, strychnine, piperine, quinine, caffeine, colchicine, coniine

Discovery — Schiff

Coniine; first alkaloid with established structure

True alkaloids in other organisms — occurrence

Rarely occur in other organisms

Fungal alkaloids (2)

Lysergic acid derivatives and sulfur-containing alkaloids are best known

Amphibian alkaloids

Many are antimicrobial

Pteridophyte alkaloids (2)

Ephedra; Taxus

Alkaloidal reagents (10)

1. Mayer’s

2. Dragendorff’s

3. Wagner’s

4. Marme’s

5. Valser’s

6. Scheibler’s

7. Sonnenchein’s

8. Picric acid

9. Tannic acid

10. Gold salt test

Mayer’s reagent

Reagent: Potassium mercuric iodide
(+): cream/yellowish precipitate

Dragendorff’s reagent

Reagent: Potassium bismuth iodide;
(+): orange precipitate

Wagner’s reagent

Reagent: Iodine in potassium iodide;
(+): reddish-brown precipitate

Marme’s reagent

Reagent: Cadmium in potassium iodide
(+): cream/yellowish precipitate

Valser’s reagent

Reagent: Mercuric iodide
(+): white precipitate

Scheibler’s reagent

Reagent: Phosphotungstic acid
(+): reddish-brown precipitate

Sonnenschein’s reagent

Reagent: Phosphomolybdic acid
(+): amorphous yellow-white precipitate

Picric acid test

(+): Mahogany red

Tannic acid test

(+): Buff-colored precipitate

Gold salt test

(+): Precipitation

Alkaloidal reagents and heavy metals

Form double salts with compounds of mercury, gold, platinum, and other heavy metals

Universal antidotes (3)

precipitates alkaloids and inhibits further absorption in the stomach

1. Tannic acid - heart of the universal antidote

2. Activated charcoal

3. Magnesium oxide

Specific Alkaloidal Tests (8)

1. Marquis

2. Hasseman

3. Vitali

4. Gulielmo

5. Gerard’s

6. Thalleoquin

7. Mandelin

8. Murexide

Marquis test

Reagent: Marquis reagent
(+): blue color
For: Codeine

Hasseman test

Reagent: Ferric chloride
(+): blood-red
For: Codeine

Vitali test

Reagent: Nitric acid
(+): gray precipitate
For: Atropine

Gulielmo test

Reagent: Sulfuric acid
(+): red with flower odor
For: Atropine

Gerard’s test

Reagent: Ethanol and mercuric chloride
(+): yellow
For: Atropine

Thalleoquin test

Reagent: Acetic acid, chlorine water, and ammonia
(+): fine blue fluorescence followed by green precipitate with ammonia
For: Quinine

Mandelin test

Reagent: Mandelin reagent
(+): violet
For: Strychnine

Murexide test

Reagent: Potassium chlorate and HCl
(+): purple color and pink on paper chromatography
For: Caffeine

Fluorescence vs Phospherescence

Fluorescence: Emits a different color under UV
Phospherescence: Substance emits color or light in the absence of light

Alkaloids — classifications (3)

1. True/typical

2. Pseudo

3. Proto

True/Typical alkaloids

Almost all compounds considered alkaloids have nitrogen atoms enclosed within a ring system
Nitrogenous heterocycle: Yes
Derived from AAs: Yes

Pseudoalkaloids

Heterocyclic alkaloids that are not derived from amino acids
Nitrogenous heterocycle: Yes
Derived from AAs: No

Protoalkaloids

Alkaloids that do not have nitrogen in a heterocyclic ring
Nitrogenous heterocycle: No
Derived from AAs: Yes

Protoalkaloids — example

Ephedrine

Alkaloids — classes according to structure (2)

1. Non-heterocyclic, or proto

2. Heterocyclic, or true/typical

Non-heterocyclic alkaloids

• lacks 1/+ properties of alkaloids in that they are feeble bases

• with nitrogen in a side chain

• alkaloids due to their physiological action rather than their chemical nature

Non-heterocyclic — examples (3)

Mescaline, ephedrine, colchicine

Heterocyclic alkaloids — groups (8)

1. Pyridine, piperidine

2. Tropane

3. Quinolone

4. Isoquinoline

5. Indole

6. Imidazole

7. Purine

8. Pyrrole, pyrrolidine

Indole alkaloid — examples (2)

Ergotamine, physostigmine

Pyrrole and pyrrolidine alkaloid — examples (2)

Hygrine, stachydrine

Shikimic acid pathway product from 3-dehydroshikimate

Gallic acid

Gallic acid pathway product

Ellagic acid - Associated with hydrolyzable tannins

CAPA and PALF mnemonics

Chorismate products: Anthraquinone, Phenol, Alcohol

Prephenate products: Aldehyde, Lactone, Flavonoid

Flavonoid example

Catechin (flavan-3-ol) - Associated with condensed/non-hydrolyzable tannins

Coumaric acid

Lactone glycoside

Cinnamic acid

Aromatic volatile oil and phenylpropanoid

Cinnamic acid + acetic acid

Catechin and non-hydrolyzable tannins

Mevalonate pathway products (4)

Non-aromatic volatile oils, cyclic and acyclic compounds, terpenoids/terpenes

Prephenate through transamination

Arogenic acid → Phenylalanine and tyrosine

Chorismate product

Anthranilic acid → Serine and tryptophan

Phenylalanine + phenyl hydroxylase

Hydroxylation produces tyrosine

Phenylketonuria

Lack of phenyl hydroxylase can affect the CNS/brain and cause mental retardation

P-coumaric acid + acetic acid

Chalcone, a flavonoid, and NHT/phlobatannin

Alkaloid synthesis

Quaternary amine + carbanion undergoes Mannich-type condensation to form an alkaloid

Pyridine-piperidine alkaloids

Traditionally called pyridine-piperidine alkaloids, although other alkaloids have other rings

Pyridine-piperidine alkaloid — occurrence

Many come from plants; some occur in insects, amphibians, and marine animals

Ornithine or aspartate (2)

Pyridine ring source;
Pyrrolidine ring source

Piperidine ring source

Lysine

Pyrrolizidine ring source

Ornithine

Pyridine-piperidine alkaloids (6)

1. Nicotine

2. Areca nut

3. Lobelia

4. Poison hemlock

5. Duboisia

6. Pituri

Nicotine

Pyridine alkaloid from Nicotiana tabaccum

Lobeline

Piperidine alkaloid from Lobelia inflata

Coniine

Piperidine alkaloid from Conium maculatum

(-)-Sparteine

Piperidine alkaloid

Nicotine — source

Nicotiana tabaccum

Nicotine — constituent

Nicotine

Nicotine — origin

Derivative of pyrrolidone

Nicotine uses (3)

1. Smoking deterrent,

2. CNS stimulant,

3. cholinergic neurotransmitter