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.
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.
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%
Cmax 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)
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.
