Chemistry of Medicinal Plants: Quinoline Alkaloids. PDF

3. Quinoline alkaloids:  Any alkaloid that possesses a quinoline, i.e., 1-azanaphthalene or benzo[b]pyridine, skeleton is known as a quinoline alkaloid, e.g., quinine. fusion the with n itrogen  Cinchona alkaloids are the only therapeutic alkaloids of...

3. Quinoline alkaloids:  Any alkaloid that possesses a quinoline, i.e., 1-azanaphthalene or benzo[b]pyridine, skeleton is known as a quinoline alkaloid, e.g., quinine. fusion the with n itrogen  Cinchona alkaloids are the only therapeutic alkaloids of this group. Quinoline alkaloids are found in the bark of different species of the Tokesare genus species genus Cinchona of the family Rubiaceae, e.g., Cinchona officinalis. Additionally, other genera in the same family contain quinoline alkaloids as well, e.g., Remijia. silent benzenefused with pyridine 2azanaphthalene isoquinoline 9929 911 L benzenes barks Wiwi  Cinchona contains about 6-10% alkaloids (~24-30 alkaloids). The most important are quinine, quinidine, cinchonine and cinchonidine. telpdiffheinsttohhemm.tt  They are found in the bark as salts of the common acid cinchotannic acid, and the special acid quinic acid that found only in the barks of Cinchona and Remijia species. afacefsticforcinchonaeremis.io  Chemistry: all of these alkaloids have the general structure, where quinoline ring (less basic) is attached through hydroxymethylene group to a quinuclidine (more basic) ring that contain a vinyl group. bicyclic system CHCH twoGmembredringsfused basic more methoxy oftheresonance ussbasicb.cz pairofelectronslessavailable Lone theotherone than havemethoxya pthey  These alkaloids are the enantiomeric pair quinine and quinidine and their desmethoxy analogs, cinchonidine (for quinine) and cinchonine (for quinidine). The stereochemistry differs at positions 8 & 9 with quinine (cinchonidine) being S,R and quinidine (cinchonine) being R,S. 27 | P a g e  levo dextro steffenemestryl totaquine bark extract  Cinchona has antimalarial and tonic prosperities. Preparations of crude cinchona alkaloids are called “totaquine” and used as antimalarial totalquinine agent. The activity is mainly due to quinine. Quinine: is the levo (-) stereoisomer of quinidine and is used as salts;  sulfate or bisulfate, hydrochloride or dihydrochloride slats. ht me bagcn - It is usedtwo form socan nitrogens two to treat some resistant strains of malaria to chloroquine. - It is given in combination with primaquine to treat relapsing vivax malaria. atnight - It is also used as analgesic agent in nocturnal leg cramps.notaccordingtotheguidelines  Quinidine: is the dextro (+) stereoisomer of quinine, used as sulfate (sparingly soluble) and gluconate (readily soluble) salts. acids acid sulfuric adf.tl ymmdagrial ofon glucoronicacid morepolauthansuifuricacid.at - It is used as a Class 1 anti-arrhythmic agent. quinine - IV of quinidine gluconate might be used in the treatment of P. falciparum malaria. 28 | P a g e  4. Isoquinoline alkaloids:derived fromquinolinealkaloids - Have an isoquinoline skeleton (isomer of quinoline), e.g., papaverine mortinitestructure and morphine (morphine has a phenanthrene nucleus as well). phenanthrene from biosynthetically - The isoquinoline backbone is biosynthesized from the aromatic amino isoquinolineroute acid tyrosine. wecan thefeatures see ofboth metabolite primary 2azanaphthalene converted topapaverine whichisasecondary authffle metabolite - Isoquinoline itself is a colorless hygroscopic liquid at room temperature. It has an unpleasant odor. It is slightly soluble in water but well soluble in ethanol, acetone, and ether. - Isoquinoline is a weak base with a pKa of 8.6. ifthereisn'tanotherN - Isoquinoline alkaloids play an important part in medicine. A number of these alkaloids are available as drugs (Table below). narial relaxation muscle smooth natural diisoquinoline hexadeca dichloride 16carbons 29 | P a g e  - The table below shows some examples of crude drugs have isoquinoline alkaloids: Crude Drug Alkaloids Opium Papaverine, narcotine Ipecacuanha Emetine, cephaline miso 1F.es Hydrastis Hydrastine, berberine Curare D-tubocurarinevery toxicneurotoxin curare s usedinnervegases isoavinoline methylated celvinoline hydroxyl 8 groups methoxy TY at p itiiiiii morphine unqongracitis.is wIl  Opium alkaloids: opium is the dried latex obtained by the incision of capsules (fruits) of Papaver somniferum, family Papaveraceae. authorityis L - It contains more than 40 alkaloids. The most important ones belong to 2 groups: isoquinoline (e.g., papaverine and narcotine), and phenanthrene (e.g., morphine, codeine and thebaine). biosyntheticallyisoquinoline - I They are found in the tissues as salts of common acids or the specific acid meconic acid. see.ienftEYdpitm Eft c to enough identify it Latex oozing drywillbewhite Meconic acid 2byautooxidation yellow black  Papaverine: - It is found in opium in a 1% yield.notthathigh - It is used mainly in the treatment of spasms and of erectile dysfunction. It is also used as a cerebral and coronary vasodilator. It may be used as a smooth muscle relaxant in microsurgery. TEITffhtf.ie relaxth inreasercnes - In pharmaceutical preparations, it is used as the water-soluble salt forms, e.g., HCl. asinjection papaverinehydrochloride 30 | P a g e  - The usual side-effects of papaverine treatment: polymorphic ventricular tachycardia, constipation, increased transaminase levels, hyperbilirubinemia and vertigo. Ym ffmsfsherelaxantastopperistalsismqs.FIgypsumalkaloids - To reduce these side-effects, some derivatives were prepared: - Ethaverine: it is the ethoxy derivative, 3x more active than papaverine and with less side-effects. kept thepharmacologicalaction - Dioxyline: it is a vasodilator. ethoxy methyl Pharth.ge lik ethox sextractedfromdiffplacesthat'swhydiffnames  Narcotine (noscapine): - It is 8-methoxy hydrastine and found in opium in a yield of 9%. It ooooooops doesn’t have any narcotic effect. assets.sioinPaticTsiEa1 qgine - It is used medicinally as a base and not as a salt. and- It is used medicinally as a cough suppressant (anti-tussive). It is as ya active as codeine and safe. morecommon  Ipecacuanha alkaloids: - Found in the roots and rhizomes of Cephaelis ipecacuanha (family Rubiaceae) underground growth PIT - The most important are 4 alkaloids: psychotrine, cephaeline, emetine and psychotrine methyl ether. - All, except emetine, are toxic and not used clinically. - However, those 3 can be converted into the medicinally active emetine. inthelab reductionemethylation the won'tconvert by plant themalltoemetine - Emetine is used as HCl salt (injection), or dichloride salt (tablets). monosalt disart twon - It is used as antiamebic, emetic and expectorant. ffce stimnetemet.ca 31 | P a g e  biosyntheticpathway Meffpellenthfes gas hydrogen under sbt on pressure in titillate aenaseweenm.mil nce 0 enzymatic pathway adoublebonds methoxy reductionemethylation abton shocks enzymaticmachinariesbetween diff beverysimilar plantscan the similar p roduce productsor the even same canbefromatropabelladona.nyosciamusn.ge atropine efEtetes fromdiffplant narcoine thanhydrastine similar dbtocks  Curare alkaloids: neurotoxinoneof the mostpoisonousnaturalproducts - The most important one is d-tubocurarine, obtained from the bark of the South American plant Chondrodendron tomentosum. Curare had been used as a source of arrow poison to hunt animals. It is used as d- tubocurarine HCl salt. they the poison arrowhead - It is used as skeletal muscle relaxant. It is neuromuscular blocking agent to secure relaxation of muscles in particular during surgery. usedinnervegases ites's ñ194 beritatives - Also, it is used to control strychnine convulsions. qq.ms xuomicaoverdoseofstrychnineaconvuisionssoin Earth ordertorelaxmuscles curarineisgiven twoisoquinolines tetrahydroisoquinoline salt quaternaryammonium onbothN ofisoquinoline 32 | P a g e  5. Phenanthrene Alkaloids: - This is the second class of opium alkaloids. The most important members of this class are: ikfi.pro tan YyY central carbon no aconolic apiii.fiagsiis angeneamnuiated ringa phenanthrene Eisoquinolinealkaloids theyareallonly basic alkaloids biosbninei.lisfaieawithit a s am hairaidic diene butarethgmeau.in 9eucaioids both aremethylated hydroxyls diacetylmorphine  Morphine: hottieahe.fm frommorphinebyacetylation  It is the only phenolic (free phenolic OH group) alkaloid in this class, and the major bioactive constituent of opium poppy seeds (~ 3 – 25% of opium). 99th's.si a99Eapnica himpfortheactivit not2ryortry  It is the first alkaloid to be isolated from plants. 4000yearsback everydiseaseis awwtheythough spiritused evil to morphine  Isolation is done based on the fact that morphine is the only opium alkaloid that has acidic phenolic OH + basic 3ry amino group. - Opium powder is soaked in lime water, Ca(OH) , for 24 hrs, where EIIwi base 2 aaneoussouionmanew.in n acidicsphenolison morphine forms water-soluble Ca salt. Other nonphenolic alkaloids precipitatee present as precipitates of free alkaloidal bases. fateEm hTt- Extraction of other alkaloids is done using organic solvents, while Ca Eating.fi nesarentacidi mwilldissoivefreebase salt of morphine remains in the aqueous layer. bacaconzi gai.FM iantget.us iiisisi racidicsartcstrongacidemeanbaselaciaificit.int b form both they - To the aqueous layer, add NH4Cl solution till pH 8-9. This range is man enough to convert morphine Ca salt into a free base (and not formasalt will with q salts the3amine convert it to the corresponding morphine HCl salt (on the basic 3ry amphotericcompound Mitishine amino group). This base precipitates in the solution. again - The precipitate (free morphine base) is filtered off and then atniiiinn.ir eiii morphinera recrystallized. 33 | P a g e NHysl morphinefree base caclzcneutralsal.tl heathines saying Pt wi outmorphine kick weaker acid   colorless avo It is solid, white, optically active (l-), water-insoluble. However, it is soluble in alkali solutions and alcohol. formsalt  Like other opium constituents (opiates), e.g., heroin, morphine acts directly on the CNS to relieve pain.  Morphine is narcotic analgesic; increases tolerance to pain and decreases perception to external stimuli, thus, it is used for the treatment of post-surgical pain and chronic pain (e.g., cancer pain), and as an adjunct to general anesthesia.  It is a standard narcotic analgesic to which other analgesics are measured. goldstandard dose eavipotent o.fm 988g onisneayqaenttotheeffectof rghYe  It is used medicinally as morphine HCl salt and morphine sulfate salt. mwithdvawlsyndromesphusicalepsycnologicalorpsuchgq.iq.ge  Side-effects include tendency to cause addiction and habituation, n impairment of mental performance, euphoria, drowsiness, loss of appetite, constipation, lethargy and blurred vision. mydriasis E e tIea  Chemical Conversions of Morphine: mestm.gl athasses 3 100narcoticanalgesic wait c tethe pe naturalbutmost codeine usedis synthesize clinically 3 methylmorphine from morphine bhntsat.de codeine p hosphate barcodeinequantity acid phosphoric iscowwhile morph isnignemorthana antitussive isneededclinically E.itaEiiiea not heroin sample only Tinie.inmfia iErins i alsoheroinmetabolized dehydration indeacetylation dediacetylationa 6 glucuronidationto 3ethylmorphine beexcretedinurine metabolism big.ge Enifemetic  All acetyl derivatives of morphine are not used medicinally because they are mor toxic and cause faster addiction than morphine.  Codeine:  It is 3-methylmorphine. It represents 0.3 – 5% of opium. 34 | P a g e  mostly  It is obtained via either extraction from opium, or methylation of morphine. onisn'tenoughtosolubilizeit alcoholic woachiral centers  It is nonphenolic, solid, water-insoluble, optically active (l-) alkaloid.  Its medicinal uses include: cough suppressant (anti-tussive), weak narcotic analgesic (only 15% of morphine. higherthanmorphine  It is used as codeine phosphate.  Thebaine: natural  It has 2 OCH3 on C-3 and C-6, and conjugated diene in ring C.  It is solid, optically active (l-) alkaloid. two  It has neither narcotic nor analgesic effects. 98 Istead of78  It can cause convulsions. It is used to prepare another opioid called demethylated oripavine, which is the parent compound from which a series of semisynthetic opioids are derived.  Apomorphine: ofthphhnolico isgaeainis.EE   It is prepared via the dehydration of morphine or codeine. It is used as HCl salt as a safe emetic drug. It induces emesis centrally via stimulating the chemoreceptor trigger zone (CTZ).  Nalorphine and Naloxone: semisynthetic notnatural  They are prepared from morphine. They are N-allyl normorphine derivatives.  They are used as HBr salts as antagonists to opiates, during opiates overdose incidents. oxidizedproduct asnarcoticanalgesic ofnatorphine  Structure-Activity Relationship (SAR) of Morphine: - To study that, several derivatives were prepared so that they have the same narcotic analgesic effect of morphine, but without the tendency for addiction. - All morphine like analgesics must have: 1) A tertiary nitrogen with a group that is reasonably small, e.g., CH3 group. Nalorphine is a complete antagonist of morphine. alsonaloxone 2) A central quaternary carbon atom (C-13). theyhavebiggerR insteadof antagonist agonist 3) A 2-carbon chain (ethyl group) separating the central carbon from the N atom. 35 | P a g e  partofthetetrahydroisoquinoline 4) Hydroxyl groups: masking the 3-OH group (the phenolic one), suppresses the activity (codeine is only 15% of morphine activity). However, masking the 6-OH group (the alcoholic one), dramatically increases the narcotic activity (heterocodeine is 600% of morphine activity). axofmorphine Acetylation of 3- and 6-OH groups (heroin) increases the activity. 5) Ether linkage is not essential for the activity. N-methylmorphinan has analgesic activity. 6) Morphine should be optically active (L-isomer is the active form) to show narcotic analgesic activity. Racemic mixture of morphine (D- and L-) is not active. withouton aether N methylon morphinane without 36 | P a g e