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

Absorption

Rapidly and well absorbed in humans following oral doses ranging from 50 to 500 mg.

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.

The Uses of N-(4-CHLOROPHENYL)-N'-(ISOPROPYL)-IMIDODICARBONIMIDIC DIAMIDE

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

Background

Proguanil is a prophylactic antimalarial drug, which works by stopping the malaria parasite, Plasmodium falciparum and Plasmodium vivax, from reproducing once it is in the red blood cells. It does this by inhibiting the enzyme, dihydrofolate reductase, which is involved in the reproduction of the parasite.

Indications

For the causal prevention and suppression of malaria caused by susceptible strains of P. falciparum and other species of Plasmodium found in some geographical areas of the world.

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.

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.

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

Proguanil is a biguanide derivative that is converted to an active metabolite called cycloguanil. It exerts its antimalarial action by inhibiting parasitic dihydrofolate reductase enzyme. It has causal prophylactic and suppressive activity against P. falciparum and cures the acute infection. It is also effective in suppressing the clinical attacks of vivax malaria. However it is slower compared to 4-aminoquinolines.

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.

Metabolism

Variably metabolized in the liver by cytochrome P450 isoenzymes to the active triazine metabolite, cycloguanil. This variable metabolism of proguanil may have profound clinical importance in poor metabolizers such as the Asian and African populations at risk for malaria infection. Prophylaxis with proguanil may not be effective in these persons because they may not achieve adequate therapeutic levels of the active compound, cycloguanil, even after multiple doses.