Biguanides and Diaminopyrimidines

Antimalarials - Synthesis and Drug Profile

a. Biguanides

Mode of action: Biguanides inhibit dihydrofolate reductase enzyme and interfere in the folic acid metabolism. This leads to inhibition of the nuclear division in malarial parasites.

Proguanil HCl (Paludrine)

Synthesis

Step I. Synthesis of p-chloro phenyl guanidine

Step II. Synthesis of isopropyl cyanamide

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

Metabolism: Proguanil is a prodrug, which is metabolized in the liver to diaminotriazine (cycloguanil) that acts as a dihydrofolate reductase inhibitor of Plasmodium species and inhibits DNA synthesis.

Properties and uses: Proguanil hydrochloride is a white crystalline powder, slightly soluble in water, sparingly soluble in ethanol, and practically insoluble in methylene chloride. It is used mainly for prophylactic treatment of malaria.

Assay: Suspend the sample in anhydrous acetic acid, shake and heat at 50°C for 5 min. Cool to room temperature, add acetic anhydride, and titrate with 0.1 M perchloric acid. Determine the end point potentiometrically.

Dose: The recommended dose as a prophylactic and a suppressant is 100 to 200 mg per day in nonimmune subjects; 300 mg/week or 200 mg twice/week in semi-immune subjects. In the case of acute vivax malaria, initial loading dose is 300 g–600 mg followed by 300 mg per day for 5–10 days. For the treatment of falciparum malaria, the dose is 300 mg two times daily for 5 days.

b. Diaminopyrimidines

Mode of Action: It inhibits the reduction of folic acid and dihydrofolic acid to the active tetrahydrofolate coenzyme form.

Pyrimethamine (Daraprim)

Synthesis

Properties and uses: Pyrimethamine exists as a white crystalline powder or colourless crystals, practically insoluble in water, and slightly soluble in alcohol. Pyrimethamine inhibits the reduction of folic acid and dihydrofolic acid to the active tetrahydrofolate coenzyme form. It finds its extensive use as a suppressive prophylactic for the prevention of severe attacks due to P. falciparum and P. vivax. It is also used in the treatment of taxoplasmosis and as an immuno suppressive agent.

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

Dose: The administered dose as a suppressive is 25 mg once a week, as a therapeutic 50–75 mg once a day for two days when used alone, otherwise 25 mg.

Dosage forms: Pyrimethamine tablets I.P., B.P.

Trimethoprim (Proloprim)

Synthesis

Properties and uses: Trimethoprim exists as a white or yellowish-white powder, very slightly soluble in water, and slightly soluble in ethanol. It is a potent inhibitor of dihydrofolate reductase. It has been employed in conjugation with sulphamethopyrazine in the treatment of chloroquine-resistant malaria. It has also been used in conjugation with sulphonamides in the treatment of bacterial infections. Trimethoprim is an antibacterial, effective against malarial parasite.

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

Dose: The administered dose is 1.5 g with 1 g of sulphametopyrazine per day for 3 days.

Dosage forms: Co-trimoxazole intravenous infusion B.P., Co-trimoxazole oral suspension B.P., Paediatric co-trimoxazole oral suspension B.P., Co-trimoxazole tablets dispersible B.P., Co-trimoxazole tablets paediatric B.P., Co-trimoxazole tablets B.P., Trimethoprim oral suspension B.P., Trimethoprim tablets B.P.