Quinoline Alkaloids PDF

Quinoline alkaloids Alkaloids containing Quinoline as their principle nucleus include those obtained from cinchona (quinine, quinidine, cinchonine and cinchonidine). Cinchona Cinchona consists of the dried bark of (Cinchona succirubra) or of its varieties.Fam...

Quinoline alkaloids Alkaloids containing Quinoline as their principle nucleus include those obtained from cinchona (quinine, quinidine, cinchonine and cinchonidine). Cinchona Cinchona consists of the dried bark of (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. 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.  Quinoline alkaloids Activities & uses 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  Quinoline alkaloids Cinchona Camptotheca acuminata Fam. Nyssaceae. 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).  Isoquinoline alkaloids Isoquinoline 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 (Isoquinoline) could be opened or enlarged. - Nine types of isoquinoline alkaloids have pharmacognostical interrest 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)  Isoquinoline alkaloids The basic biosynthetic reactions of these compounds result from the Mannich-condensation of Phenylethylamine with keto derivatives. The Phenylethylamine is obtained from phenylalanine or The carbonyl derivative could be aliphatic tyrosine or 3,4-dihydroxy L-phenylalanin after decarboxylation. aldehyde or alpha-keto acid The lead to : -formation of simple tetrahydro-isoquinoline alkaloids *Isoquinoline alkaloids are widespread in the following - iridoid (biosynthesis of monoterpenoid- isoquinoline plant families, Aristolochiaceae, Magnoliaceae, alkaloids - emetine type) or phenylacetaldehyde derivative (biosynthesis Lauraceae, Menspermaceae, Ranunculaceae, of benzylisoquinoline alkaloids. Papaveraceae (Papaver, Argemone, Chelidonium) and Fumaraceae. - The bisbenzylisoquinoline molecules - The important drugs which contain such alkaloid of this group are: Opium, Ipecac, Hydrastis, Curare, and Berberis.  Isoquinoline alkaloids 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  Isoquinoline alkaloids Opium (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.  Isoquinoline alkaloids Opium (Crude) 1 -Morphine Structure-activity relationship of morphine: Introduction of a hydroxyl Substituents on the N-atom are crucial; the group at C-14 increases the replacement of the methyl group by small alkyl analgesic activity. radicals (e.g. allyl, cyclopropylmethyl, cyclobutylmethyl) transforms the compound into a partial or a complete opioid antagonist The inversion of the Esterifications or etherification configuration at C-9 and of the hydroxyl group at C-3 C-13 makes the activity decreases the analgesic activity. disappear.  Isoquinoline alkaloids Opium (Crude) 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 a function of the route of administration: very fast (5-7 minutes) by IV injection, maximal by intrathecal injection (12-24 hours). - Morphine depresses the cough center. It causes myosis. Morphine acts on the pituitary to decrease the secretion of FSH, LH and ACTH - Morphine can be used as starting material for the synthesis of apomorhine (as emetic drug used), and of nalorphins (morphine antagonist, antidote by atemdepression caused by morphine).  Isoquinoline alkaloids Opium (Crude) 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 the respiratory centers, a slight broncho-constriction due to a direct effect on smooth muscles, a decrease in secretions, and a release 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 or paracetamol.  Isoquinoline alkaloids Opium (Crude( 3 -Papaverine It conceder to be one of Benzylisoquinoline type Papaverine is an alkaloid found in opium but not closely related to the other opium alkaloids in its structure or pharmacological actions Pharmacological activities and use 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, and to 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). 4It is also used to treat the CVA (cerebrovascular accidents), the symptoms of ischemia in the eye, and symptoms of arteritis in the lower legs.  Isoquinoline alkaloids Opium (Crude( 4 -Noscapine Its one of Phthalidisoquinoline type 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.  Isoquinoline alkaloids Ipecac alkaloids Source 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. Contents 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.  Isoquinoline alkaloids Ipecac alkaloids Alkaloids of Ipecac H3CO - Emetine is the major constituent of Rio Ipecac (60-75%) OCH3 NH OCH3 of the total alkaloids) but it forms only 30-50% of the H3CO total alkaloids of Cartagena Ipecac. N Reduction Emetine - The other alkaloids possess similar chemical structures: Methylation Methylation cephaline (monophenolic) and psychotrine. H3CO OCH3 H3CO OCH3 NH OCH3 HO NH OCH3 HO - It is the fact that cephaline on methylation gives emetine H2 N and psychotrine on reduction gives cephaline. Reduction N Psychotrine Cephaline  Isoquinoline alkaloids 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  Isoquinoline alkaloids Curare Alkaloids Curare Alkaloids are group of isoquinoline alkaloids belonging to Bis-benzyltetrahydroisoquinolines type. Source It is a crude dried extract from the bark and stems of Strychnos castelnaei, Strychnos toxifera, 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 woorari for 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.  Isoquinoline alkaloids Curare Alkaloids A-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. curine - 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. chondrocurine. isochondrodendrine  Isoquinoline alkaloids Curare Alkaloids b-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  Alkaloids of Phenylalkylamine Biosynthetic Source: Alkaloid-like amines. Have no nitrogen as part of the It derived from Phenylalanine amino acid heterocyclic ring. Distribution : This group of alkaloids occurs in many plants and can be classified into the followings: a. Beznylamine type (e.g. the capsaicinoids) b. Phenylethylamine Type (e.g. mescaline) c. 2-aminophenylpropane type (e.g. ephedrine, cathinone) N R R N N R R R R Benzylamine type Phenylethylamine-type 2-Aminophenylpropane-type  1 - Ephedra Alkaloids  Various Ephedra species, e.g. E. sinica (Ephedraceae).  Ephedra used as remedy forAsthma in Chinese medicine  Contains 2% alkaloids e.g. ephedrine, Pseudoephedrine, norpseudoephedrine. R R R HO-C-H HO-C-H HO-C-H R R S CH3-NH-C-H H-C-NH-CH3 H-C-NH2 CH3 CH3 CH3 L-Ephedrine D-Pseudoephedrine D-Norpseudoephedrine  (-)-Ephedrine is the major Alkaloid in Ephedra.  Ephedrine is a phenylalkylamine with N atom in the side chain  Ephedrine is similar to adrenaline in structures. Advantages of Ephedrine over adrenaline: 1- Orally active. 2 - Prolonged action HO * * CH CH CH3 HO CH CH2 OH NH CH3 OH NH CH3 Ephedrine Adrenaline Pharmacology: ephedrine is an indirect sympathomimetic, close to adrenaline Uses: in asthma, allergic drugs, bronchodilator, nasal congestion and in cough mixtures  2 - Capsicum Ripe fruit of Capsicum annum (Solanaceae). Contains 1.5% Capsainoids (amides of vanillylamines with satrurated or unsaturated C8-C13 fatty acids). O H 3C O R Capsaicine R= N O H Dih yd rocapsa icine R= O HO Nordihydrocapsaicine R= Uses: as carminative, counterirritant in the form of tincture or plaster in the treatment of rheumatism and neuralgic pains Test: 1 - solution of capsaicine + FeCl3 green color 2 - Capsaicine + H2SO4+ small amount of sugar violet color after period of 1 h  3 - Khat Leaves of Catha edulis (Celastraceae). in fresh leaves cathinone, in the dried cathine Pharmacology: It causes anorexia, hyperthermia, respiratory stimulation, mydriasis, arrhythmia and hypertension. It induces the release of catecholamines.