Pharmacognosy II (PHG322) 1 PHG322, Alakloids1

PHG 322: Course Description The following subjects will be covered: 1- Plants containing Alkaloids (botanical and chemical character) Introduction Examples of medicinally important Alkaloids and their importance as “Lead Compounds” from the following groups: Phenylalkylamine , Tropolone, Imidazole, Pyridine, Piperidine, Tropane, Quinoline, Isoquinoline, Opium, Indole, Carboline, Purine and Steroidal alkaloids. 2- Marine Derived Drugs Introduction, Biomedical potential of marine natural products Biologically active substances from marine source (Anticancer, Antiviral, Antimicrobial, Antiparasitic and Antiinflammatory active compounds). PHG322, Alakloids1

PHG 322: Course Description The following subjects will be covered: 3- Plants containing Glycosides (botanical and chemical characters) Introduction, Examples of medicinally important Glycosides and their importance as a “Lead Compounds” from the following groups: Cardiac glycosides, Saponins glycosides, Anthracene derivatives, flavonoidal glycosides and related compounds, & Cyanogenic glycosides, thioglycosides and phenylpropan-derivatives. 4- Toxicological Pharmacognosy (Poisonous plants) Introduction, Poisonous plants, important toxic plants affecting: nervous system, cardiovascular system, gastrointestinal tract, respiratory system. PHG322, Alakloids1

PHG 322: Course Description The following subjects will be covered: 5- Herb-Drug interactions Mechanisms of Drug Interaction with Herbs. Problems Monitoring Herb-Drug Interaction. Herb-Drug Interactions reports: cardiovascular system, central Nervous System, pain Killers and anti-inflammatory drugs PHG322, Alakloids1

Required Text book Pharmacognosy, Trease and Evans, ترجمة منصور السعيد و محمد اليحيى، المركز العربي للتعريب والترجمة والنشر – دمشق، 2003 Pharmacognosy and Pharmacobiotechnology, Williams & Wilkins, 1996. PHG322, Alakloids1

Alkaloids PHG322, Alakloids1

Deviation from Definition: Alkaloids, which mean alkali-like substances, are basic nitrogenous heterocyclic compounds of plant origin generally possessing a marked physiological action. Deviation from Definition: Some alkaloids are not basic e.g. Colchicine, Piperine, quaternary alkaloids Few alkaloids contain nitrogen in a non-ring system e.g. Ephedrine, Colchicine. Mescaline 3) Plant origin: Some alkaloids are derived from bacteria, fungi, insects, frogs, animals. PHG322, Alakloids1

Classification 4- False alkaloids 3- Pseudo alkaloids 1- True alkaloids - Derived from amino acid. - Nitrogen atom is a part of heterocyclic ring. 2- Proto-alkaloids - Nitrogem atom is not a part of heterocyclic ring. 3- Pseudo alkaloids - Not derived from amino acid. - Nitrogen atom is a part of hetrocyclic ring. 4- False alkaloids - non alkaloids give false positive reaction with alkaloidal reagents. PHG322, Alakloids1

Distribution and occurrence: Rare in lower plants. Dicots are more rich in alkaloids than Monocots. Families rich in Alkaloids: Apocynaceae, Rubiaceae, Solanaceae and Papaveracea. Families free from Alkaloids: Rosaceae, Labiatae Function in Plants: They may act as protective against insects and herbivores due to their bitterness and toxicity. They are, in certain cases, the final products of detoxification (waste products). Source of nitrogen in case of nitrogen deficiency. They sometimes act as growth regulators in certain metabolic systems. They may be utilized as a source of energy in case of deficiency in carbon dioxide assimilation. PHG322, Alakloids1

Distribution in Plants All Parts e.g. Datura. Barks e.g. Cinchona Seeds e.g. Nux vomica Roots e.g. Aconite Fruits e.g. Black pepper Leaves e.g. Tobacco Latex e.g. Opium PHG322, Alakloids1

Forms of Alkaloids Free bases Salts with Organic acids e.g. Oxalic, acetic acids Salts with inorganic acids e.g. HCl, H2SO4 Salts with special acids e.g. Meconic acid in Opium, Quinic acid in Cinchona Glycosidal form e.g. Solanine in Solanum. PHG322, Alakloids1

Nomenclature of Alkaloids Trivial names of alkaloids should terminate with the suffix: (ine) Their names may be derived from: Genus name e.g. Atropine from Atropa. Species name e.g. Cocaine from Coca. Common name e.g. Ergotamine from Ergot. Physiological activity e.g. Emetine (emetic). Discoverer e.g. Pelletierine from Pelletier. PHG322, Alakloids1

Nomenclature of Alkaloids (Contin..) Prefixes and suffixes: These are, usually, added to the name of the parent alkaloid and are used to designate related alkaloids, generally present in the same plant. Examples are: Prefixes: "Nor-" designates N-demethylation or N-demethoxylation, e.g. norpseudoephedrine and nornicotine. "Apo-" designates dehydration e.g. apomorphine. "Iso-, pseudo-, neo-, and epi-" indicate different types of isomers. Suffixes: "-dine" designates isomerism as quinidine and cinchonidine. "-ine" indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine. PHG322, Alakloids1

Physical Properties 1- Condition: 2- Color: Most alkaloids are crystalline solids. Few alkaloids are amorphous solids e.g. emetine. Some are liquids that are either Volatile e.g. nicotine and coniine, or Non-volatile e.g. pilocarpine and hyoscine. 2- Color: The majority of alkaloids are colorless but some are colored e.g.: Colchicine and berberine are yellow. Canadine is orange. The salts of sanguinarine are copper-red. PHG322, Alakloids1

Physical Properties (Contin..) 3- Solubility: Both alkaloidal bases and their salts are soluble in alcohol. Generally, the bases are soluble in organic solvents and insoluble in water. Salts are usually soluble in water and, insoluble or sparingly soluble in organic solvents. Exceptions: Bases soluble in water: caffeine, ephedrine, codeine, colchicine, pilocarpine and quaternary ammonium bases. Bases insoluble or sparingly soluble in certain organic solvents: morphine in ether, theobromine and theophylline in benzene. Salts insoluble in water: quinine monosulphate. Salts soluble in organic solvents: lobeline and apoatropine hydrochlorides are soluble in chloroform. PHG322, Alakloids1

Physical Properties (Contin..) 4- Isomerization: Optically active isomers may show different physiological activities. l-ephedrine is 3.5 times more active than d-ephedrine. l-ergotamine is 3-4 times more active than d-ergotamine. d- Tubocurarine is more active than the corresponding l- form. Quinine (l-form) is antimalarial and its d- isomer quinidine is antiarrythmic. The racemic (optically inactive) dl-atropine is physiologically active. PHG322, Alakloids1

Chemical Properties 1- Nitrogen: 2- Basicity: Primary amines R-NH2 e.g. Norephedrine Secondary amines R2-NH e.g. Ephedrine Tertiary amines R3-N e.g. Atropine Quaternary ammonium salts R4-N⁺ e.g d-Tubocurarine 2- Basicity: R2-NH > R-NH2 > R3-N Saturated hexacyclic amines are more basic than aromatic amines. PHG322, Alakloids1

Chemical Properties (Contin..) Quaternary ammonium ion N in alkaloids → in form of amine Primary amino group Secondary amino group Tertiary amino group Quaternary ammonium ion e.g. Norpseudo-ephedrine Ephedrine Nicotine Tubocurarine PHG322, Alakloids1

Factors influencing the degree of basicity: Structure of the molecule Presence & position of other substituents & functional groups e.g. degree of unsaturation of heterocyclic ring Pyridine Piperidine Electron withdrawing gps Electron releasing groups e.g. carbonyl group e.g. alkyl group Piperidine alkaloids → more basic than pyridine alkaloids decrease basicity increase basicity unsaturation decreases basicity PHG322, Alakloids1

Chemical Properties (Contin..) According to basicity alkaloids are classified into: Weak bases e.g. Caffeine Strong bases e.g. Atropine Amphoteric → due to the presence of acidic group(s) e.g. Phenolic Alkaloids or Alkaloids with Carboxylic groups e.g. Morphine e.g. Narceine Neutral alkaloids e.g. Colchicine PHG322, Alakloids1

Chemical Properties (Contin..) 3- Oxygen: Most alkaloids contain Oxygen and are solid in nature e.g. Atropine. Some alkaloids are free from Oxygen and are mostly liquids e.g. Nicotine, Coniine. 4- Stability: A- Effect of heat: Alkaloids are decomposed by heat, except Strychnine and caffeine (sublimable). PHG322, Alakloids1

Chemical Properties (Contin..) B- Reaction with acids: Salt formation. Dil acids hydrolyze - Ester Alkaloids e.g. Atropine and Glucoalkaloids e.g Solanine C- Conc. acids may cause: Dehydration: e.g Atropine to Apoatropine and Morphine to Apomorphine Demethoxylation: e.g. Codeine PHG322, Alakloids1

Chemical Properties (Contin..) C- Reaction with alkalies: 1- Dil alkalis They liberate most alkaloids from their salts e.g. NH3. They may cause isomerization (racemization) of alkaloid e.g. the conversion of hyoscyamine to atropine. They also can form salts with alkaloids containing a carboxylic group e.g. narceine. 2- Strong alkalis: such as aqueous NaOH and KOH They may form salts with phenolic alkaloids. They hydrolysis Ester alkaloids (e.g. atropine, cocaine and physostigmine) and Amide alkaloids ( colchicines). They cause opening of lactone ring e.g. Pilocarpine. PHG322, Alakloids1

Chemical Properties (Contin..) D- Effect of light and Oxygen: Some alkaloids are unstable when exposed to light and Oxygen: PHG322, Alakloids1

Detection and characterization A- Precipitation by certain reagents 1-  Mayer’s reagent (potassium-mercuric iodide) yellowish-white precipitate. 2-  Dragendorff’s reagent (potassium-bismuth iodide) gives orange red recipitate. 3-  Wagner’s reagent (potassium triiodide) forms red flocculent precipitate. B- Color reactions with certain reagents 1-  Froehd’s reagent (sulphomolybdic acid) 2-  Marqui’s reagent (formaldehyde + H2SO4) 3-  Mandalin’s reagent (sulphovanadic acid) 4-  Mecke’s reagent (selenic acid + H2SO4) 5-  Erdmann’s reagent (HNO3 + H2SO4) PHG322, Alakloids1

Extraction, Purification and Isolation of Alkaloids Method I: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents. Method II: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities. Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases. PHG322, Alakloids1

Classification of Alkaloids Biogenetic. Based on the biogenetic pathway that form the alkaloids. Botanical Source. According to the plant source of alkaloids. Type of Amines. Primary, Secondary, Tertiary alkaloids. Basic Chemical Skeleton tropane, quinoline, imidazol, isoquinoline, etc… alkaloids. PHG322, Alakloids1

Basic nucleus or skeletons of alkaloids Phenylalkylamines alkaloids e.g. Ephedrine Pyridine and piperidine alkaloids e.g. lobeline, nicotine Tropane alkaloids e.g. Atropine. Quinoline alkaloids e.g. quinine and quinidine PHG322, Alakloids1

Basic nucleus or skeletons of alkaloids Isoquinoline alkaloids e.g. papaverine Phenantheren alkaloids e.g. Morphine Indole alkaloids e.g. ergometrine Imidazole alkaloids e.g. pilocarpine PHG322, Alakloids1

Basic nucleus or skeletons of alkaloids Purine alkaloids e.g. caffeine Steroidal alkaloids e.g. Solanum and Veratrum alkaloids Terpenoid alkaloids e.g. Taxol PHG322, Alakloids1

Drugs containing pyridine alkaloids Examples of drugs containing alkaloids Drugs containing pyridine alkaloids PHG322, Alakloids1

Classification of Pyridine Alkaloids Pyridine alkaloids can be classified according to the building nucleus into: Pyridine nucleus only Pyridine nucleus + another nitrogenous ring Tetrahydro-pyridine nucleus Piperidine nucleus Pyridone nucleus PHG322, Alakloids1

Classification of Pyridine Alkaloids Pyridine alkaloids can be classified according to the building nucleus into: This type of alkaloids could be divided into 4 subgroups and the nucleus of the molecule is one of the following nuclei: 1- Pyridine alone: e.g. trigonelline 2- Pyridine with other nitrogenous rings (e.g. pyrrol-ring) e.g. tobacco alkaloids 3- Tetrahydropyridine e.g. areca alkaloids 4- Pyridone e.g. ricinine PHG322, Alakloids1

Drugs containing pyridine alkaloids Tobaccos The leaves of the tobacco plant Nicotiana tabacum (Fam: Solanaceae) are used for production of Cigarettes. They are toxic plants which contain alkaloids, chiefly represented by nicotine. Other close structurally alkaloids have been found such as nornicotine, the N-oxidized derivatives of nicotine, e.g. nicotyrine, anabasine and anatabine. PHG322, Alakloids1

Tobacco-alkaloids: Identification 1- Volatile liquid alkaloids ► 4-6% several volatile, non-volatile and crystalline alkaloids: 1- Volatile liquid alkaloids e.g. nicotine, nor-nicotine, anabasine and anatabine. 2- Non-volatile liquid alkaloids e.g. nicoteine and nicotyrine 3- Solid-alkaloids e.g. nicotelline Identification 1- Nicotine + p-dimethylaminobenzaldehyd + HCl gives rose-red color. 2- aq. Solution of nicotine + acidic vanillin gives red color. 3- aq. Solution of nicotine + formaldehyde + HNO3 gives red color. PHG322, Alakloids1

Examples of Tobacco alkaloids air or light Colourless or pale yellow oily liquid brown Nicotine non-volatile liquid Volatile liquids (-)-nicotine (major) nicoteine nor-nicotine PHG322, Alakloids1

Pharmacology: (nicotinic) receptors. Nicotine possesses a high affinity to the gangionic-cholinergic (nicotinic) receptors. So, it stimulates all autonomic ganglia. It acts on the CNS causing tremors and convulsions. It also stimulates the respiratory and vomiting centers. It acts on the smooth muscle of the intestine, by increasing tone and motor activity. It acts on the cardiovascular system, by inducing vasoconstriction and an increase in arterial blood pressure. In the long run, nicotine is responsible for the genesis of cardiovascular and pulmonary diseases. It is used in the form of chewing gum or transdermal system for relieving the symptoms of withdrawal of cigarettes. It is also used as insecticide and anthelmintic in veterinary medicine. It increases incidence of abortion. PHG322, Alakloids1

Drugs containing Pipiridine alkaloids PHG322, Alakloids1

1- Black Pepper dried fruits of Piper nigrum (Fam. Piperaceae), a perennial plant in (India and cultivated also in Indonesia, Sri Lanka and South America). The pungent taste is due to piperidine amides (5-10 %). The chief constituent is piperine (insecticide), an amide of piperidine and of piperic acid. The other amides are piperidines (piperanine, piperettine, piperolein A and Piperolein B), pyrrolidines (piperyline). Piperidine Piperine PHG322, Alakloids1

PHG322, Alakloids1

Piperine: Colorless, odorless needles or prisms with burning taste, insoluble in H2O, soluble in alcohol, chloroform and ether. Exhibits only weak basicity (no salt with acid). On hydrolysis, gives piperidine and piperic acid. Used as stomachic and insecticide. Has CNS depressant and anticonvulsant effects in rats. Identification of Piperine: 1- On the addition of Wagner’s reagent, steel blue needle crystals of piperine periodide are formed. 2- Piperine on treating with platiniumchloride solution gives orange red needles. 3- Piperine on treating with H2SO4 gives a red color. PHG322, Alakloids1

2- Pomegranate The plant is a shrub widespread Punica granatum (Fam. Punicaceae). The bark contains 0.5- 0.7% total alkaloids: (-) pelletierine, isopelletierene, and N-methylated analogs. The plant is used as anthelmintic.. PHG322, Alakloids1

3- Lobelia alkaloids The dried aerial parts of Lobelia inflata (indian tobacoo). The major alkaloid is Lobeline. It is used in the treatment of asthma, chronic bronchitis and in anti-smoking preparations. Injection of lobeline hydrochloride is used in the resuscitation of newborn infants. Caution: Toxic doses of the herb has a paralytic effect. PHG322, Alakloids1