| Identification | Back Directory | [Name]
N-(4-CHLOROPHENYL)-N'-(ISOPROPYL)-IMIDODICARBONIMIDIC DIAMIDE | [CAS]
500-92-5 | [Synonyms]
bigumal
paludrine
PROGUANIL
Aids008307
Aids-008307
chlorguanide
chloroguanide
ChlorguanideCl
Chlorguanide-D6Cl
Chlorguanide-d6 HCl
637-32-1 (Hydrochloride)
Diguanyl (hydrochloride)
1-(p-chlorophenyl)-5-isopropyl-biguanid
1-(p-chlorophenyl)-5-isopropylbiguanide
1-(4-chlorophenyl)-5-isopropylbiguanide
Chlorguanide (base and/or unspecified salts)
N-(4-CHLOROPHENYL)-N'-(ISOPROPYL)-IMIDODICARBONIMIDIC DIAMIDE
Imidodicarbonimidic diamide, N-(4-chlorophenyl)-N'-(1-methylethyl)- | [EINECS(EC#)]
207-915-6 | [Molecular Formula]
C11H16ClN5 | [MDL Number]
MFCD00866201 | [MOL File]
500-92-5.mol | [Molecular Weight]
253.73 |
| Chemical Properties | Back Directory | [Melting point ]
129° | [Boiling point ]
399.65°C (rough estimate) | [density ]
1.2039 (rough estimate) | [refractive index ]
1.6110 (estimate) | [storage temp. ]
Store at -20°C, protect from light | [solubility ]
DMF: 2mg/mL; DMSO: 3mg/mL; DMSO:PBS (pH 7.2) (1:10): 0.09mg/mL; Ethanol: 1mg/mL | [form ]
A solid | [pka]
11.15±0.10(Predicted) |
| Hazard Information | Back Directory | [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. |
| Questions And Answer | Back Directory | [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.
|
| Safety Data | Back Directory | [Safety Profile]
Poison by ingestion,
intravenous, and intraperitoneal routes.
Experimental reproductive effects. When
heated to decomposition it emits toxic
fumes of Cland NOx. |
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