8-Amino quinolines

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Chapter: Medicinal Chemistry : Antimalarials

8-Amino quinolines: Primaquine (Primaquine Phosphate) , Pamaquine


Antimalarials - Synthesis and Drug Profile

8-Amino quinolines

Mode of action: While the mechanism of action of the 8-amino quinolines is unknown, it is known that primaquine can generate reactive oxygen species via an autoxidation of the 8-amino quinoline group with the formation of radical anion. As a result, cell destructive oxidants, such as hydrogen peroxide, super oxide, and hydroxyl radical can be formed.

 

Primaquine (Primaquine Phosphate)


Synthesis

Step I. Preparation of 1-phthalimido-4-bromo pentane


Step II. Synthesis of 8-amino-6-methoxy quinolone


Step III. Condensation of product of Step I and Step II


Metabolism: Primaquine is totally metabolized by CYP3A4 with primary metabolites having carboxy primaquine. Trace amounts of N-acetyl primaquine, aromatic hydroxylated products, and conjugation metabolites are seen.


Properties and uses: Primaquine is a crystalline powder, soluble in water, and practically insoluble in alcohol. In vitro and in vivo studies indicate that the stereochemistry at the asymmetric carbon is not important for antimalarial activity. These appears to be less toxicity with the levorotatory isomer, but this is dose–dependent, and may not be of much importance as the doses used to treat exoerythrocytic P. vivax malaria. It is extensively used for the radical cure of relapsing vivax malaria, but it is not normally employed either for arresting the severe attacks of the disease or for the suppressive therapy. It invariably kills gametocytes of all the species, or inhibits their growth and development in the mosquito. It fails to produce any significant effect on other erythrocytic stages, and hence, it must not be employed alone for the treatment of malaria.

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

Dose: The recommended dose for administration is 17.5–26.3 mg (10–15 mg of base) once daily for 14 days.

 

Pamaquine


Synthesis


Properties and uses: It was the first 8-amino quinoline marketed, used as an antimalarial agent.

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