بسم الله الرحمن الرحيم PHG 322 Pharmacogonsy II lecture 2 Presented by Assistant Prof. Dr. Ebtesam Alsheddi

Stability: hot dil. acids or conc. mineral acids may cause: Generally alkaloids are decomposed by heat except: caffeine sublimes without decomposition Effect of Acids: hot dil. acids or conc. mineral acids may cause: Dehydration O-demethylation Next page ! e.g. codeine apoalkaloids conc HCl or HI e.g. morphine apomorphine morphine + CH3Cl or CH3I

Stability: (cont.) hot dil. acids or conc. mineral acids may cause: Effect of Acids: (cont.) hot dil. acids or conc. mineral acids may cause: Hydrolysis of - glucoalkaloids: - ester alkaloids: e.g. solanine e.g. atropine

Effect of strong alkalies liberate most alkaloids from their salts Stability: (cont.) Effect of Alkalies: Effect of weak alkalies Effect of strong alkalies Effect of hot dil. alkalies liberate most alkaloids from their salts form salts with alkaloids containing carboxylic group e.g Narceine + NaHCO3 Na salt

hydrolysis of ester alkaloids b) Effect of strong alkalies: salt (phenates) phenolic alkaloid + aq. NaOH or KOH c) Effect of hot dilute alkalies: hydrolysis of ester alkaloids cleavage of lactone ring corresponding acid e.g. atropine e.g. pilocarpine Pilocarpic acid

Precipitation reactions precipitating reagent (contains heavy metals Tests for identification: include two types of reactions: Precipitation reactions Colour reactions 1) Precipitation reactions: precipitating reagent aqueous soln. of alkaloidal salts + (contains heavy metals e.g. Hg, Cd, Bi, …) Coloured ppts (amorphous or crystalline) N.B. certain alkaloids do not react e.g. caffeine false positive results are possible most reagents precipitate: proteins, tannins, …

Classification of Alkaloidal precipitating agents: 1- Reagents that form double salts: a- Mayer’s Reagent: Potassium Mercuric Iodide. b- Dragendorff’s Reagents: Potassium Iodobismethate. c- Gold Chloride. 2- Reagents Containing Halogens: a- Wagner’s Reagent: Iodine/ Potassium Iodide. 3-Organic Acids: a- Hager’s Reagent: Picric Acid b- Tannic Acid. 4- Oxygenated High Molecular Weight Acids: a- Phosphomolybdic acid b- Phosphotungestic acid c- Silicotungestic Acid

+ Colour Reagents: 1- Froehd’s Reagent: Phosphomolybdic acid 2- Marqui’s Reagent: Formaldehyde/ Conc. H2SO4 3- Mandalin’s Reagent: Sulphovanidic acid 4- Erdmann’s Reagent: Conc. HNO3/Conc. H2SO4 5- Mecke's Reagent: Selenious acid / conc. H2SO4 6- Shaer's Reagent: Hydrogen peroxide / conc. H2SO4 7- Rosenthaler's Reagent: Potassium arsenate / conc. H2SO4 8- Conc. HNO3 solid (free base) colour reagent + characteristic colour (contain conc H2SO4 + an oxidizing agent) These tests are sensitive to micro amounts used for colourimetric determination (quantitative)

- specific for one alkaloid or a group of related alkaloid: 1) Vitalis test for solanaceous alkaloids: + conc HNO3 & alc. KOH violet colour 2) Van-Urks test for ergot alkaloids: + PDAB in conc H2SO4 blue colour

Pharmacological activity N.B. + ve with: - most alkaloids Pharmacological activity: wide range of pharmacological activities Pharmacological activity Alkaloid Analgesic & narcotics Morphine Anti-tussive Codeine CNS stimulant Caffeine & strychnine Mydriatic Atropine Anticancer Vincristine, vinblastine, taxol 10

Chemical classification: Non-heterocyclic Heterocyclic = Atypical alkaloids (Protoalkaloids) = typical alkaloids 14 major groups according to ring structure

Pyridine nucleus + another nitrogenous ring Alkaloids of the Pyridine nucleus: classified according to building nucleus into: Pyridine nucleus only Pyridine nucleus + another nitrogenous ring Tetrahydro-pyridine nucleus Piperidine nucleus Pyridone nucleus 12

1) Pyridine alkaloids containing another nitrogenous ring: e.g. Tobacco alkaloids non-volatile liquid Volatile liquids (-)-nicotine (major) nicoteine nor-nicotine

Nicotine Colour tests 2 basic N atoms form salts with acids Properties: air or light Colourless or pale yellow oily liquid brown less basic Colour tests aq. soln + PDAB 2 basic N atoms rose red colour form salts with acids violet colour gradually Tests: nicotine + picric acid Crystals

respiratory stimulant Pharmacological actions & uses: due to high toxicity Little use in medicine In small doses respiratory stimulant In larger doses respiratory depressant Increases incidence of abortion Main use: Insecticide & anthelmintic in veterinary medicine

2) Piperidine alkaloids: e.g. alkaloids of: a) Black pepper b) Conium c) Lobelia d) Pomogranate a) Pepper alkaloids: Occurrence: fruits of Piper species e.g. P. nigrum Major alkaloid: piperine + acid It is very weak basic No salt Colour tests + H2SO4 Red colour

Crystal tests soluble in: CHCl3 & EtOH insoluble in: H2O Piperine + alc KOH Piperidine + Piperic acid Crystal tests alc. soln. + Wagner`s reag. blue crystals

Uses: Chronic toxicity: Mainly as condiment Little use in medicine Used in rubefacient preparations Chronic toxicity: Prologed use at high doses loss of taste buds in tongue

c- Lobelia alkaloids Occurrence: the dried aerial parts of Lobelia inflata.(indian tobacoo) Major alkaloid: Lobeline crystalline)

Uses: -Asthma -Chronic bronchitis -Anti-smoking preparations -Injection of lobeline hydrochloride is used in the resuscitation of newborn infants. Caution: Toxic doses the herb has a paralytic effect

d- Pomegranate alkaloid Occurrence: the fruit rind, root bark and stem bark of Punica granata Major alkaloid: pelltierine (liquid) pelletierine tannate (mixture, solid) Alkali decompose it to give free alkaloids Pomegranates have astringent properties because of the alkaloids (pelletierine tannate) present in the bark of the stems and roots and have been used for many years as an anthelmintic: removing tapeworms

II. Alkaloids of the Quinoline group Most important → Cinchona alkaloids Cinchona alkaloids Present in the bark Cinchona species - Cinchona ledgeriana & C. calisaya (yellow Cinchona) - C. succirubra (red Cinchona) F. Rubiaceae e.g. of alkaloids: two groups of stereoisomers: Quinine (l) & Quinidine (d) Cinchonidine (l) & Cinchonine (d) > 50%

Cinchonine & cinchonidine Quinine (Cinchonidine epimer at C-9) Quinidine (Cinchonine epimer at C-9) Structure: R Alkaloid H Cinchonine & cinchonidine OCH3 Quinine & quinidine (few drops till yellow colour appears) Quinine: Intensely bitter solid

1) Fluorescence test: + dil H2SO4 Fluorescence Quinine (l) gives Quinidine (d) among other products when warmed with KOH in amyl alcohol Cinchonine & Cinchonidine are less soluble in H2O than quinine & quinidine Test: 1) Fluorescence test: + dil H2SO4 Fluorescence + ve for quinine & quinidine 2) Thalleoquine test: aq. soln of alkaloidal salt + Br2/H2O + NH4OH Emerald green colour

Uses: Quinine (contra indicated in pregnancy as it causes abortion) as Quinine sulphate or other salts used as anti-malarial has febrifuge effect (contra indicated in pregnancy as it causes abortion) used as Quinidine cardiac depressant (anti-arrythmic) Cinchonine and Cinchonidine are used as anti-rheumatic

Structure activity relationship: For antimalarial activity (Quinine): - Removal of vinyl group loss of activity - Replacement of CHOH by: - CHCl, CH2, CO decreases activity Vinyl group

III. Alkaloids of the Isoquinoline group Ipecacuanha Opium (Papaverine type)

Isoquinoline Alkaloids 1- Ipecacuanha Alkaloids Occurrence: Ipecac is the dried roots and rhizomes of Cephalis ipecacuanha (Brazilian ipecacuanha) or Cephalis acuminata (Cartagena or Panama ipecacuanha) Fam. Rubiaceae. It contains several alkaloids (2 –2.5 %), mainly emetine (50- 70 % of total alkaloids), with cephaline and psychotrine.

It is non phenolic and levorotatory. It contains 2 basic nitrogens. Emetine: It is non phenolic and levorotatory. It contains 2 basic nitrogens. Cephaline: It is phenolic and levorotatory. It gives emetine on methylation with (CH3)2 SO4. Psychotrine: Occurs as yellow prisms. It is phenolic and gives cephaline on reduction. It gives emetine on reduction followed by methylation.

Tests for identification of Ipeca alkaloids: Alkaloidal solution in HCl + Ca hypochlorite  orange color. Emetine and cephaline + Froehd's reagent: dirty green color (the color with emetine fades by addition of HCl). Psychotrine + Froehd's reagent: pale green color. Cephaline and psychotrine + p-nitrodiazobenzene  dye soluble in NaOH  purple color. Psychotrine + conc. H2SO4 + HNO3  cherry red color. Emetine + Liebermann's reagent  black color.

Uses: Emetine and cephaeline have antitumour and antiviral activity, but are too toxic for therapeutic use. Emetine and psychotrine are mainly used as emetic drugs. The crude drug is used as expectorant (due to its saponin content) . Emetine HCl has an antiamoebic effect, and are used for the treatment of amoebic dysentry and Fasciola. Ipeca alkaloids are diaphoretic, alone or in combination with opium (e.g. Dover's powder).