4-Substituted Quinolines

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Chapter: Medicinal Chemistry : Antimalarials

4-Substituted Quinolines : Chloroquine (Nivaquin, Aralen, Lariago), Amodiaquine HCl (Camoquin), Hydroxy chloroquine (Plaquenil)

Antimalarials - Synthesis and Drug Profile

4-Substituted Quinolines

Mode of Action: Three different mechanism of actions are suggested for these drugs:

DNA interaction: The mechanism of action for quinine is that the drug gets intercalated into the DNA of the parasite. It is based on the fact that the concentration required for the inhibition of nucleic acid synthesis is significantly higher than that necessary for the inhibition of the plasmodium parasite.

Ferriprotoporphyrin IX: The plasmodium parasite utilizes host haemoglobin as a source of amino acid. On digestion of the haemoglobin, the haem is released as ferriprotoporphyrins IX and it produces haemoly sis of the erythrocyte parasites. Therefore, ferriprotoporphyrin that is released is converted into nontoxic products and they, in turn, to haemozoites by the polymerase enzyme. The steps involved in the conversion to haemozoites are inhibited by the chloroquine.

Weak base hypothesis: The 4-substituted quinolines have weak base and because of this pKa they are thought to accumulate in a location, which is acidic (parasite lysozome pH 4.8–5.2). As the extracellular fluid of the parasite is at pH 7.4, the weak base will move towards a more acidic pH of lysosome. Once the acid–base reaction occurs, elevating the pH in the lysozome, that in turn reduces the parasite’s ability to digest haemoglobin, thus reducing the availability of amino acids.

Metabolism of Quinine: It is metabolized in the liver to 2-hydroxy derivative followed by additional hydroxylation on the quinoline ring with the 2,3-dihydroxy derivative, as the major metabolite. This metabolite has low activity and is rapidly excreted in urine.

Properties and uses: Quinine hydrochloride exists as fine, silky needles, often in clusters, colourless, soluble in water and in alcohol. It is used in the treatment of malaria.

Assay: Dissolve the sample in alcohol, add 0.01 M hydrochloric acid, and titrate with 0.1 M sodium hydroxide. Determine the end point potentiometrically.


Chloroquine (Nivaquin, Aralen, Lariago)


Step I. Synthesis of 4,7-dichloro quinolone

Step-II: Preparation of 1-diethyl amino-4-amino pentane

Step III. Condensation of the products of Step I and Step II

Metabolism: The drug is metabolized by N-dealkylation through CYP2D6, and CYP3A4 isoenzymes. It has been reported that the level of metabolism correlates closely with degree of resistance.

Properties and uses: Chloroquine exists as white or almost white crystalline powder, soluble in water and in methanol, very slightly soluble in ethanol. It is mainly used as an antimalarial. Chloroquine also has antihistaminic and antiinflammatory properties. It is used to treat hepatic amoebiasis, rheumatoid arthritis, discoid lupus erythematosus, cutanea tards, solar urticaria, and polymorphous light eruptions. Chloroquine and other 4-amino quinolines are not effective against exoerythrocytic parasites. It is an example for poor selective toxicity. Adverse reactions include retinopathy, haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency (same mutation that confers resistance against malaria), muscular weakness, exacerbation of psoriasis and porphyria, and impaired liver function.

Assay: Dissolve the sample in anhydrous acetic acid and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The recommended dose as a prophylactic and a suppressive is 500 mg once per week. As a therapeutic the dose , initially, is 1 g followed by 500 mg in 6 h, and 500 mg on the 2nd and 3rd day.

Dosage forms: Chloroquine sulphate injection I.P., B.P., Chloroquine sulphate tablets I.P., B.P.


Amodiaquine HCl (Camoquin)


Properties and uses: It exists as yellow crystalline powder with a bitter taste, and is soluble in water. It is very similar to chloroquine and does not have any advantages over the other 4-amino quinoline drugs. It is used for suppressing P. vivax and P. falciparum infections being 3–4 times more active than quinine.

Dose: The recommended dose initially is 600 mg followed by 300 mg doses 6, 24, and 48 h later.


Hydroxy chloroquine (Plaquenil)


Step I. Preparation of side chain-N-ethyl-N-(2-hydroxyethyl)-4-amino pentylamine

Step II. Condensation of the product of Step I with 4,7-dichloro quinolone

Properties and uses: Hydroxychloroquine is a white or almost white crystalline powder, soluble in water, practically insoluble in ethanol and in ether. It is equivalent to the chloroquine, but it is less toxic and used in the place of chloroquine against normally sensitive strains. It is mainly used as an antimalarial. It is also used for the treatment of rheumatoid arthritis and lupus erythematoses.

Assay: Dissolve the sample in water, add 1 M sodium hydroxide, and extract with dichloromethane. Combine the dichloromethane extracts and evaporate. Add anhydrous acetic acid and titrate against 0.1 M perchloric acid, using oracet blue B solution as indicator.

Dose: In P. falciparum infections, the dose is 1.25 g in a single dose or in two divided doses at 6 h intervals; in rheumatoid arthritis, 400 mg daily; in lupus erythematosus, 200 to 400 mg 1 or 2 times daily.

Dosage forms: Hydroxychloroquine tablets B.P.

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