N-(4-CHLOROPHENYL)-N'-(ISOPROPYL)-IMIDODICARBONIMIDIC DIAMIDE

Pharmacology and mechanism of action

Proguanil (PG) was introduced as a prophylactic agent against malaria just after the Second World War. It is a pyrimidine derivative which is highly active against pre-erythrocytic forms of Plasmodium (P) falciparum making it suitable for casual prophylaxis. It is also effective in the erythrocytic phase (schizontocide) against all forms of malaria, but the action is too slow for the drug to be used for treatment. Proguanil prevents the formation of sporozoites in the mosquito, thus interfering with the spread of malaria ^[1]. The drug acts through an active metabolite (cycloguanil). The mechanism of action is due to an inhibition of dihydropholate reductase^[2].
Like most other antimalarials, the efficacy of proguanil has been reduced by the development of resistence. Already during the 1950s and 60s P. falciparum resistance was reported from all endemic areas including Africa ^[1]. In P. vivax and P. malariae, resistence seems less frequent but resistent strains have been reported in Malaysia, Indonesia, and Taiwan ^[1]. Partial crossresistance occurs with other antifolates, particularly with pyrimethamine.

Indications

Proguanil is used in combination with chloroquine as chemoprophylaxis against falciparum malaria in areas with a low frequency of resistance, i.e. tropical Africa.
 

Side effects

Proguanil is well tolerated in recommended doses and severe side effects are not reported in persons with a normal kidney function^[3]. Several reports of mouth ulceration due to proguanil have, however, been reported ^{[4, 5]}, and mild epigastric discomfort may occur.
 

Contraindications and precautions

Dosage adjustments are necessary in patients with kidney failure ^[6].
 

Interactions

Chloroquine may increase the risk of mouth ulceration with proguanil ^[7].
 

Preparation

Available as proguanil hydrochloride: 100 mg hydrochloride equals 87 mg base.
 
• Paludrine® (Zeneca). Tablets 100 mg.
 

References

1. Black RH, Canfield CJ, Clyde DF, Peters W, Wernsdorfer WH (1986). Proguanil and proguanil analogues. In: Chemotherapy of Malaria, 2nd edn, edited by L.J.Bruce-Chwatt. (Geneva: World Health Organization), pp. 71–77, 110–111.
2. Ferone R, Burchall JJ, Hitchings GH (1969). Plasmodium berghei dihydrofolate reductase. Isolation properties and inhibition by antifolates. Mol Pharmacol, 5, 45–59.
3. Proguanil. Therapeutic Drugs, edited by Sir Colin Dollery (1991), (London: Churchill Livingstone), pp. P247–P251.
4. Mulley G (1974). Proguanil and mouth ulcers. Lancet, 2, 873.
5. Daniels AM (1986). Mouth ulceration associated with proguanil. Lancet, i, 269.
6. Boots M, Phillips M, Curtis JR (1982). Megaloblastic anaemia and pancytopenia due to proguanil in patients with chronic renal failure. Clin Nephrol, 18, 106–108.
7. Drysdale SF, Phillips-Howard PA, Behrens RH (1990). Proguanil, chloroquine, and mouth ulcers. Lancet, 355, 164.

Description

Chloroguanide is active with respect to exoerythrocyte and erythrocyte forms of plasmodia. It is most beneficial for suppressive therapy. It is used for preventing malaria, and it should be started 2 weeks before entering a malarial zone and should be taken for 8 weeks. Synonyms of this drug are biguanide, bigunal, paludrine, proguanil, and others.

Uses

Proguanil is medicaments; used in preparation of pyrrolecarboxamide derivatives as anti-malarial agents.

Indications

Chloroguanide hydrochloride (Paludrine) is activated to a triazine metabolite, cycloguanil, which also interferes with parasite folic acid synthesis. It is a dihydrofolate reductase inhibitor that is used for the prophylaxis of malaria caused by all susceptible strains of plasmodia. Chloroguanide is rapidly absorbed from the gastrointestinal tract. Peak plasma levels occur 2 to 4 hours after oral administration, and the drug is excreted in the urine with an elimination half-life of 12 to 21 hours. Its side effects and spectrum of antimalarial activity are quite similar to those of pyrimethamine.The conversion of chloroguanide to the active metabolite is decreased in pregnancy and also as a result of genetic polymorphism in 3% of whites and Africans and 20% of Asians.

Definition

ChEBI: A biguanide compound which has isopropyl and p-chlorophenyl substituents on the terminal N atoms. A prophylactic antimalarial drug, it works by inhibiting the enzyme dihydrofolate reductase, which is involved in the reproduction of the malaria parasites Plasmodium falciparum and P. vivax within the red blood cells.

brand name

Paludrine (Zeneca).

Antimicrobial activity

Proguanil has low antiplasmodial action, but useful activity is attributable to the metabolite cycloguanil, which inhibits the early erythrocytic stages of all four Plasmodium spp. that cause human malaria and the primary hepatic stage of P. falciparum. Proguanil acts synergistically with atovaquone and probably enhances its effect on mitochondrial membrane charge.

Acquired resistance

Resistance of P. falciparum associated with point mutations of dihydrofolate reductase has been reported worldwide. Resistance in P. vivax and P. malariae has been reported in South East Asia. Cross-resistance with pyrimethamine is not absolute, because differential resistance can arise from different point mutations on the dihydrofolate reductase gene.

Pharmaceutical Applications

A synthetic arylbiguanide, formulated as the hydrochloride for oral use. It is slightly soluble in water.

Pharmacokinetics

Oral absorption: >90%
C_max 100 mg oral: 0.4 mg/L after 2–4 h
Plasma half-life: 10 h
Plasma protein binding: 75%
Oral absorption is slow. It is 75% protein bound and is concentrated 10- to 15-fold by erythrocytes. About 20% of the drug is metabolized to dihydrotriazene derivatives, most importantly cycloguanil,by hepatic cytochrome P₄₅₀ processes. Cycloguanil is detectable 2 h after administration of proguanil. High proportions of ‘non-metabolizers’ have been identified in Japan and Kenya, indicating another source of resistance. About 60% of the dose is excreted in the urine.

Clinical Use

Antimalarial prophylaxis (usually in combination with chloroquine)
Treatment and prophylaxis for drug-resistant falciparum malaria (in combination with atovaquone)

Side effects

It is well tolerated at recommended doses. Gastrointestinal and renal effects have been reported at doses exceeding 600 mg per day.

Safety Profile

Poison by ingestion, intravenous, and intraperitoneal routes. Experimental reproductive effects. When heated to decomposition it emits toxic fumes of Cland NOx.

Synthesis

Chloroguanide, N1 -(4-chlorophenyl)-N5 -isopropylbiguanide (37.1.3.2), is made from 4-chloroaniline and sodium dicyanoamide, the interaction of which results in the formation of (4-chlorophenyl)dicyanodiamide (37.1.3.1). Reacting this with isopropylamine gives the desired chloroguanide.

In in vitro conditions, chloroguanide is not active, although in the organism it transforms to an active dihydrotriazine compound.

Raw materials

Preparation Products