Alkaloids: Definition, Occurrence, and Naming

• Alkaloids are difficult to define due to their chemical, biochemical, and physiological diversity.
• It encompasses organic nitrogenous compounds found in plants, animals, fungi, and bacteria.
• These substances can be lab synthesized and often exhibit marked physiological activity.
• Most alkaloids display basic properties because of the presence of an amino nitrogen.

Alkaloid Occurence in Plants

• Seeds such as nux vomica and areca may contain alkaloids.
• Fruits including black pepper and conium can contain alkaloids.
• Leaves, as seen in belladonna leaf and hyoscyamus, are sources of alkaloids.
• Underground stems of sanguinaria and corydalis may contain alkaloids.
• Roots such as aconite and belladonna root may possess alkaloids.
• Rhizomes and roots of ipecac and hydrastis are alkaloid sources.
• Barks like cinchona and pomegranate can contain alkaloids.
• Fungi like ergot are also known to contain alkaloids.

Naming Conventions for Alkaloids

• Alkaloid names originate from the generic name of the plant eg, hydrastine, atropine.
• The specific plant name gives rise to alkaloid names eg, cocaine, belladonnine.
• Common drug names relate to alkaloid names eg, ergotamine.
• The physiological activity of the compound e.g., emetine, morphine influences naming.
• Discoverers are another source of alkaloid names e.g., pelletierine.
• Chemical convention dictates that alkaloid names end in "ine".

Toxicity of Alkaloids

• Animal intoxication often results from accidental ingestion of alkaloid-containing plants.
• The amount of alkaloid ingested and sensitivity of the animal are key factors.
• Certain alkaloids are extremely harmful to mammals.
• Cyclopamine, a steroidal alkaloid, causes teratogenic effects in lambs via Veratrum californicum.

Possible Functions of Alkaloids in Plants

• Alkaloids may act as poisonous agents, protecting plants from insects and herbivores.
• They serve as end products of detoxification reactions, metabolically locking up harmful compounds.
• Alkaloids may have regulatory functions for growth.
• They can serve as reserve substances, supplying nitrogen or other elements to the plant.

Pharmacological Actions of Alkaloids

• Some alkaloids like morphine and codeine are analgesics and narcotics.
• Others such as strychnine and brucine act as central stimulants.
• Atropine and homatropine are mydriatics whereas physostigmine and pilocarpine are myotics.
• Ephedrine causes a rise in blood pressure, while reserpine can lower it in excessive hypertension.
• These extensive physiological activities show the versatile pharmacology of alkaloids.

Properties of Alkaloids

• Most alkaloids are crystalline substances that form salts when combined with acids.
• In plants, they can be found either in a free state or as salts or N-oxides.
• Organic compounds containing the functional group N+-O- are known as amine oxides, which are weak bases, highly polar, found to be hydrophilic, and possess excellent water solubility].
• Most alkaloids contain oxygen, along with carbon, hydrogen, and nitrogen.
• Some additional alkaloids lack oxygen in their molecules -- coniine, nicotine, and sparteine which are liquids.
• Colored alkaloids are rare.
• Berberine is yellow and sanguinarine salts are copper-red.

Additional Properties of Alkaloids

• Alkaloids typically contain one nitrogen atom but some ergotamine can contain up to five.

• The nitrogen may exist as a primary, secondary, or tertiary amine.

• The nitrogen atom bears an unshared pair of electrons.

• These molecules are basic, resembling ammonia in chemical properties with varying degrees of basicity.

• Like ammonia, alkaloids can be converted into salts by aqueous mineral acids.

• Free amine is liberated when the alkaloid salt reacts with hydroxide ion, nitrogen gives up a hydrogen ion.

• Quaternary ammonium compounds [R4N+ X-] like tubocurarine chloride or muscarine chloride have four organic groups covalently bonded to nitrogen and the positive charge of this ion is balanced by some negative ion.

• Quaternary ammonium ions are not affected by hydroxide ions, thus have different chemical properties from amines.

• Alkaloids are generally insoluble or sparingly soluble in water, but their salts are freely soluble.

• Free alkaloids are usually soluble in ether, chloroform, or other nonpolar, immiscible solvents.

• Alkaloidal salts are insoluble in these solvents

• This difference in solubility is used for the isolation, purification, and quantitative estimation of alkaloids.

Tests for Alkaloids

• Most alkaloids are precipitated from neutral or slightly acidic solutions by:

• Mayer's reagent, which is potassium mercuric iodide solution.

• Wagner's reagent, which is a solution of iodine in potassium iodide

• Solution of tannic acid

• Hager's reagent a saturated solution of picric acid

• Dragendorff's reagent , which is a solution of potassium bismuth iodide

• Precipitates can either be amorphous or crystalline and have a variety of colors such as cream (Mayer's), yellow (Hager's), and reddish-brown (Wagner's and Dragendorff's)..

• Care is required when applying these tests because reagents also precipitate with proteins.

• Some proteins denature and become insoluble and thus can be filtered out.

• Caffeine and other purine derivatives do not precipitate like most alkaloids.

• Caffeine is detected by mixing with potassium chlorate and hydrochloric acid, evaporating to dryness, and exposing the residue to ammonia vapor.

• The resulting purple color is the murexide test.

Biosynthesis of Alkaloids

• Alkaloid structures can be rationalized through chemical reactions involving amino acids.
• Important reactions include decarboxylation and transamination of amino acids to form amines/aldehydes.
• Amines and Aldehydes can react to form a Schiff base which can react with a carbanion in a Mannich type of condensation.

Major Amino Acids in Alkaloid Biosynthesis

• Ornithine
• Lysine
• Phenylalanine
• Tyrosine
• Anthranilic acid
• Tryptophan

Classification of Alkaloids (Hegnauer's classification)

• True alkaloids are derived from amino acids and contain nitrogen in a heterocyclic ring e.g., Atropine.

• Protoalkaloids come from amino acids but do not have nitrogen in a heterocyclic ring e.g., Ephedrine.

• Pseudo alkaloids are not derived from amino acids but do contain nitrogen in a heterocyclic ring e.g., Caffeine.

• False alkaloids are non-alkaloids that react positively with alkaloid reagents e.g., homatropine.

• Classification can also be based on the ring structure/nucleus of the chief alkaloid group in the plant drug:

  • Pyridine-piperidine combined.
  • Tropane
  • Quinoline
  • Isoquinoline
  • Indole
  • Imidazole
  • Steroid
  • Lupinane
  • Alkaloidal amine
  • Purine

Alkaloid Classification by Chemical Structure

• Alkaloids are categorized based on the nature of the basic chemical structures from which they are derived.
• Examples of Alkaloid structures:
  • Pyridine and Piperidine Derivatives: arecoline, pelletierine, lobeline, coniine, nicotine.
  • Tropane Derivatives: atropine, hyoscyamine, hyoscine -condensation product of pyrrolidine and piperidine.

Alkaloid Nuclei

• Cinchona alkaloids (quinine, quinidine, cinchonine, cinchonidine) contain quinoline.
• Hydrastine, d-tubocurarine, emetine and certain Opium alkaloids are characterized by the isoquinoline nucleus.
• Ergonovine, reserpine, strychnine derive from the indole ring.
• Pilocarpine possesses the imidazole ring.
• Caffeine and theobromine are purine bases.
• Morphine and codeine possess the phenanthrene ring.
• Aconitine and protoveratrine contains a steroidal structure.

Extraction of Alkaloids

• Utilizes fractional extraction from less polar to more polar compounds.
• Defatting occurs using a non-polar solvent like petroleum ether, benzene, or alkane to extract chlorophyll, waxes, volatile oils, and fixed oils.
• Filtration is performed using marc, then methanol or 95% ethanol. Rotary evaporation then concentrates the sample.
• Adding 2% tartaric acid and ethyl acetate separates week or neutral alkaloids into an organic layer.
• An aqueous layer (acidic, containing tartaric acid) with alkaloidal salts forms.
• Adding NH3 or Sodium bicarbonate breaks the salt, then adding ethyl acetate separates again into two layers.
• An aqueous layer contains Quaternary alkaloids (4°).
• The organic layer contains basic alkaloids (1°, 2°, 3°).

Purification of alkaloid extracts

• Direct crystallization: The extract is evaporated to dryness & the residue is dissolved in a crystallizing solvent.
• Solubility order: Hexane, benzene, ether, ethyl acetate, methanol, acetone, chloroform & dioxane.
• Steam distillation is used in rare cases, for liquid alkaloids, e.g. coniine, nicotine & sparteine.
• Crystallization of sparingly soluble salts.
  • The choice of acid is unlimited, but HCl, HBr, oxalic, picric, perchloric, sulfuric, maleic, tartaric acids are among the widely used acids.
  • Hydro halides are generated dissolving the crude base in methanol or acetone & adding an ethereal solution of the acid.
  • Oxalates, picrates & perchlorates are usually formed by mixing methanolic solutions of the base & the acid.
• Distribution between immiscible solvents the alkaloids are in a dilute acid solution
  • Alkaloids may be recovered by adding ammonium hydroxide solution & extracting with water-immiscible organic solvent.
  • Organic solvent choice is usually limited to benzene, chloroform, or ether.

Pyridine, Piperidine, and Pyrrolidine Alkaloids

• Upon reduction, the tertiary base pyridine is converted into the secondary base piperidine.

• These two nuclei create the basis for this group which is divided into three:

  • Derivatives of piperidine eg, lobeline from lobelia.
  • Derivatives of nicotinic acid eg, arecoline from areca.
  • Derivatives of both pyridine-pyrolidine eg, nicotine from tobacco.

• Biosynthesis of pyridine- piperidine alkaloids is as follows for Nicotine:

  • Ornithine is incorporated into nicotine by tobacco plants.
  • The incorporation results in a symmetric labelling pattern of nicotine.

• The N-methylpyrrolinium ion is a key intermediate, attaching to C-3 of the pyridine ring of nicotinic acid via electrophilic aromatic substitution.

Drugs Containing Pyridine-Piperidine Alkaloids

Tobacco: Nicotiana Tobacco

• It is dried leaves of Nicotiana tobacco F: Solanaceae.
• The substance is cultivated for smoking.
• It contains alkaloids from 0.6-0.9%, mainly nicotine.
• Nicotine is an oily liquid alkaloid, colorless but oxidizes to yellow.
• Nicotine has complex pharmacologic actions by binding to receptors in autonomic ganglia, the adrenal medulla, neuromuscular, junction, and the brain.
• Chronic use of nicotine leads to psychologic and physical dependence.
• Nicotine impacts the cardio vascular system causing peripheral vasoconstriction, atrial tachycardia and both systolic & diastolic blood pressure increase.
• 50% of all smokers die of heart disease and 20% of lung cancer.
• The carcinogenicity of tobacco results for a potent carcinogen N-nitroso nor nicotine.
• N-nitroso nor nicotine is found in cigarettes, cigars & chewing tobacco at levels in the range of 2-90pp (parts per billion).
• N-nitrosamines are considered hazardous to health.

Lobelia or Indian Tobacco

• Lobelia is dried leaves & tops of Lobelia inflate F: Lobeliaceae (Campanulaceae).
• This drug contains 14 alkaloids, and a large number of piperidine and N-methylpiperidine derivatives: lobeline, lobelanine, and lobelanidine.
• Lobeline is the major alkaloid.
• Lobeline occurs in colorless crystalsslightly soluble in water, and readily soluble in hot alcohol.
• Galenical preparations of Lobelia were formerly used for expectorant purposes.
• Lobeline acts as a respiratory stimulant, however its effects are questionable with an unreliable and brief duration.
• Other effects resemble nicotine.
• 0.5 to 1.5 mg doses of lobeline sulfate are incorporated in tablets or lozenges intended to break the tobacco habit.
• It is used in applications in the treatment of drug addictions such as addiction to amphetamines, cocaine or alcohol.

Areca of the Areca Catechu Plant

• Areca is the dried, ripe seed of Areca catechu (Fam. Palmae) and contains several alkaloids.
• Arecoline (arecaidine methyl ester)
• Arecaidine (N- methyl guvacine)
• Guvacine (tetrahydronicotinic acid)
• Guvacoline (guvacine methyl ester)
• Total alkaloids reach up to 0.45%.
• Arecoline Hydrobromide is an anthelmintic drug used in veterinary medicine against parasitic worms.
• Arecoline is a parasympathomimetic (agonist) acting on muscarinic receptors and at high doses, on nicotinic receptors.
• Results of its impact include vasodilation, hypotension, and reflex tachycardia at low doses-stimulation of intestinal tone and peristalsis-increase in secretions,hypersalivation and sweating-myosis-bladder contraction.

Pomegranate

• Pomegranate root and stem bark/Granatum is derived from Punica granatum (Fam. Punicaceae).
• It contains about 0.5-0.9% of liquid alkaloids.
• Pelletierine and pseudopelletierine form the chief liquid alkaloids, alongside 22% of tannin.
• Pelletierine tannate, a mixture of the tannates of the alkaloids, featured in the BP 1948 and was an anthelmintic prescribed for tapeworms.

Conium

• Conium is the full grown but unripe fruit of Conium maculatum F: Umbellifareae.
• It includes coniine and conhydrine.
• The plant is poisonous for humans and animals.
• Accidental ingestion yields central nervous system depression, respiratory failure, acute rhabdomyolysis, acute renal failure, or death.
• Conium's effect on the neuromuscular junction yields non-depolarizing blockers (similar to curare).

Piper

• Consists of dried full grown unripe fruit of Piper nigrum F: Piperaceae.
• Contains up to 4.5-8% of piperine.
• It it used a condiment.
• Black pepper comes from the unripe fruits of Piper nigrum
• White pepper comes from the ripe fruits.
• Piper has irritant, stimulant & febrifuge activity (decrease body temperature).
• Piperine possesses a piperidine moiety combined with piperic acid through an amide function.
• On hydrolysis of piperine gives another alkaloid piperidine which is a liquid alkaloid.

Tropane Alkaloids

• The principal alkaloids of medicinal interest in this group are (*)-hyoscyamine.
• The group is inclusive of a more stable racemate atropine, and hyoscine (scopolamine).
• The compounds are esters and are hydrolyzed by heating at 60°C with baryta water (an aqueous solution of barium hydroxide.
• Atropine yields tropic acid and tropine.
• Hyoscine produces tropic acid and oscine (scopine is actually formed by enzymatic hydrolysis but the chemical treatment converts it to the more stable geometric isomer, oscine).
• Tropane Alkaloids are poisonous.
• Tropane is a bicyclic amine, incorporating pyrrolidine and piperidine rings, sharing a common nitrogen atom and 2 carbon atoms.
• • It is a dicyclic compound formed by condensation of a pyrrolidine precursor (ornithine) with three carbon atoms derived from acetate.
• Both the pyrrolidine and piperidine ring systems are recognizable in the Tropane compound.
• Tropine is the 3-hydroxy derivative of tropane of tropane is known.
• Esterification of tropine and (-)-tropic acid produces hyoscyamine (tropine-tropate) ester.

Biosynthesis of Tropane Alkaloids

• Feeding studies, involving labelled ornithine, reveal the amino acid is incorporated stereospecifically in order to form the pyrrolidine ring of tropine.
• The remaining three C atoms derive from acetate thus giving the piperidine moiety a completion.
• Methylation transmethylates from a donor, e.g. methionine, to give the tropine nucleus.
• Esterification of tropic acid with tropine gives hyoscyamine.

Tropane alkaloids

• Solanaceous Tropane Alkaloids.
• Erythroxylon (Coca) Alkaloids

Solanaceous Tropane Alkaloids

• The (-)-isomer is hyoscyamine and the (+)-isomer is not found in the plant
• Atropine is the racemic of hyoscyamine; it is the (±)-isomer Atropine.
• Hyoscyamine is more potent than atropine.
• Scopolamine/ Hyoscine is an epoxide of atropine and it is the (-)-isomer.
• The (±)-isomer of scopolamine is atrosine.
• 200 tropane alkaloids have been recorded.
• Semi synthetic derivatives e.g. N-butyl bromide (buscopan) are of medicinal value.

Drugs containing tropane alkaloids

Belladonna plant

• The parts of the plant that make it "official" are its roots and leaves
• It is the dried leaf or root of Atropa belladonna F: Solanaceae
• Roots are richer in alkaloids. This is since their level is 0.6% whilst the leaves lie below 0.4%.
• Most of the alkaloids are the (-) hyoscymine and some traces of atropine in fresh plant. during racemization the extraction is a process by which atropine is formed
• Small amount of other bases are found in the root not the leaf. These include the anhydride of atropine (apoa tropine) and its stereoisomer belladonnine and scopolamine/ hyoscine.
• Belladonna acts as a parasympathic depressant.
• Possesses anticholinergic properties. To take note is excess motor activity of the gastro intestinal and spasm of the urinary tract.
• Decreases intestinal tone and paralyzes the uterus.
• It decreases the flow of more secretion.
• Saliva, milk, sweat are types of secretion mentioned.
• In the eyes, alkaloid influences passive mydriasis,
• In the heart atropine rises increases the heart rate by suppressing vagal inhibition.
• No effects of blood pressure
• It has blood vessels the effects of blood vessels.
• Cutaneous capillaries may observe due to toxic face.

Hyoscyamus or Henbane :

• The dried leaves & flowering tops of Hyoscyamus niger F: Solanaceae.

• The dru contains 0.04% of total alkaloids calculated as hyscyamine and traces of atropine.

• Hyoscyamus is a parasympatholytic, crude drug but is rarely employed in medicine today.

• Egyptian Henbane:

  • The dried leaves & flowering tops of Hyoscyamus muticus.
  • High alkaloid, yield amount of of 1.5% of total alkaloids consiting largely of hyoscyamine.
  • Is indigenous in Egypt -The plant is only used for the extraction of its alkaloids in Egypt.

Stramonium (Datura stramonium)

The dried leaves & flowering tops of Datura stramonium F: Solanaceae.

• The active properties stem from 0.4% of total alkaloids calculated as hyoscyamine.
• Stramonium has action like that of belladonna
• The powdered substance's an ingredient used in preparations which are intended to be burned and the vapor inhaled for the relief of asthma.

Medical Uses

• These drugs serve as mydriatics-dilating the pupils.
• They are antispasmodic.
• They can be parasympatholytic/anticholinergic, reducing secretions.
• It is an adjunctive therapy of peptic ulcer functional digestive disorder & diarrhea.

Cocaine Biosynthesis

• Feeding experiment with Erythroxylon show that phenylalanine is incorporated into cocaine, being placed in the benzoyl group.
• Presumably, the eagonine moiety derives from ornithine and acetate much like tropine biosynthesis.

Cocaine

• Cocaine stems from the habit of forming drugs derived from Erythroxylum coca F: Erythroxylaceae.

• Coca can also be the plant's other source of name.

• Coca leaves contain all or 3 basis types of alkaloids

  • Derivatives of eagonine
  • Tropine
  • Hygrine

• The active products stem from mainly Cocaine.

• Is the methyl aster of benzoyl

• Cocain/ hydrochloride are agents of abuse & Inhales well in the pharyngeal mucosa.

• Cocaine is the most significant stimulant.

• Cocaine is a local at the surface ( 2-5 percent).

Quinoline alkaloids

• The alkaloids mainly containing quinoline consist of alkaloids exclusively from Cinchona bark

  • The alkaloids that make up the members
  • quinine.
  • Quinidine.
  • cinchonine.
  • cinchonidine.

• Quinoline derivatives such as Chiconchona Caligaya, Ledgerians ,Rubacea have more then twenty five alkaloids.

Basic Structures of Cinchona Alkaloids:

• Usually has two rings quinoline and bicyclic quinolidine.
• Rubanol which is created by a combination of distinct heterocy.
• A methyl quinoline and queuelidene has distinct methyl.

Key structural compounds

• Quinine and qunidine are steroismers

• The same structure is shon that differ in atom arrangements.

• For cinchonic/ quinidine C8=R

• C9=for chinoiodines/ quinenie, C9=R

• Stereoisomers are similar molecule that differ only, in terms atom arrangement are space.

• It is used I have a medical application.

• Quinoline derivatives such as Chiconchona Caligaya, Ledgerians ,Rubacea have more then twenty five alkaloids

• Studies with geraniol and tryptophan suggest that guanine is relatedly derived from monoterpenoids trip pathways.

• Quinine/ Quinidine

• Quinidine C8=S

• Cincha C8=. quinidine/ quinine molecules.

• Studies in metabolic pathway test in in test. • Fluorescnence test: the the the quinidine, in acid (sulpuric, etc),.

•Add of a of quinine salt/ ammonia.

•Quine/ Quinidine .

• Quinidine in the world.

•Test result in point sensitive, can detect, 0.00/% for example:

• The drug has high use of 600 mg.

Uses of Chicona Alkaloids

• Cinchone & its alkaloid, have the use in, treatment of fever ,for many years.

•Quin has the use a maleria. . Quinine is to treat, arrhythmias, tachycardia and fibrill, contractions as well in atrial quinidine is the is salts that

• Depress heart

In regard to alkaloids/ their toxicity's

• Chiconism or qualism
• Quinine . it's results of treat in product will use the .
• Hearing ringing (or .
• If these happens a of condition happens this .
• It includes side headache pain , and skin reactions.
• Ring in each ears
• Isoquinoline alkaloids*** The composition of the following compound consist of :
• Isoquiline.

+The following are what is about isoquiline: •It is a a that has .

•There many of has types as of

•The and the.

Tetra hydro

• Tetra hydro has and.
• What of this type
• -and a of from a. •The important

• What consist and use, and: •Are and The and There . ###Uses: are /in 3.

OPIUM

• Opuim the of .

• Term poppy Latin produce

• OPIUM and is the

• Cultivation .

• The term is a is a

###Cultivation

• ,
• spring.
• each 50/
• The •Morphine code 4 20percent
• 4/percent
• Opium also color of test. •Opiod test test

of classification:.

• Phen .

• The are .

• The that •Morphine use are so. and .

CH

• Morphine.

• . morphine

• .

• , a to by. "N. morphine., are . and

• The: