All of these compounds are inhibitors of dihydrofolate reductase in bacteria, plasmodia, and humans. Fortunately, they have a significantly high affinity for bacterial and protozoan dihydrofolate reductases. Pyrimethamine, for example, inhibits parasite dihydrofolate reductase at levels several hundred times lower than required to inhibit dihydrofolate reductase in humans. This is the basis of their selective toxicity. The selective toxicity can be increased upon supplying additional folic acid to the host organism, which the parasite cannot use. In fact, diaminopyrimidines (trimetoprim, pyrimethamine) were initially suggested as medicinal and preventative drugs against malarial infections. It was shown that all powerful inhibitors of dihydrofolate reductase can remove the malarial parasite with relatively minor consequences in the host.
As was already stated, biguanides and diaminopyrimidines are active against exoerythrocyte and erythrocyte forms for plasmodia. Each of these drugs can be used individually for prevention; however, the maximal effect is achieved when used in combination with sulfonamides.
It has been shown that a few sulfones and sulfonamides may be of interest as drugs for treating malaria. Experimental research uncovered the pronounced synergism between sul-fonamides and chloroguanide and pyrimethamine.
Chloroguanide: Chloroguanide, ^1-(4-chlorophenyl)-^5-isopropylbiguanide (22.214.171.124), is made from 4-chloroaniline and sodium dicyanoamide, the interaction of which results in the formation of (4-chlorophenyl)dicyanodiamide (126.96.36.199). Reacting this with iso-propylamine gives the desired chloroguanide [30-32].
/== CN N" (CH3)2CHNH2 /=\ NH NH CH3 Cl^^^— NH2 + Na-N-CN -- Cl—^—NH-C—NH—CN -» NH-C"NH-C-NH-CH(^
In in vitro conditions, chloroguanide is not active, although in the organism it transforms to an active dihydrotriazine compound.
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.
Pyrimethamine: Pyrimethamine, 2,4-diamino-5-(4'-chlorophenyl)-6-ethylpyrimidine (33.1.60), is described in Chapter 33.
This powerful inhibitor of dihydrofolate reductase is used for preventing and treating malaria caused by plasmodia P. vivax, P. malariae, P. ovale, including P. falciparum.
Pyrimethamine, an antagonist of folic acid, exhibits antimicrobial action against causative agents of malaria and simultaneously possesses sporontocide action. It is also effective with respect to the causative agent of toxoplasmosis. It is used for preventing malaria and treating toxoplasmosis. It can only be used for preventative measures; however, because resistance develops quickly and because of the fact that the maximal effect is achieved by using it in combination with sulfadoxine, a combined drug which is prescribed under the name fansidar, which contains a pyrimethamine-sulfadoxine ratio of 1:20.
A combination of pyrimethamine, sulfonamide, and quinine is the drug of choice for acute attacks of malaria and its chloroquine-resistant forms.
Pyrimethamine in combination with sulfadiazine or trisulfapyrimidine is the drug of choice for toxoplasmosis. A synonym of this combined drug is daraprim.
Other antimalarial drugs: The malaria parasite is sensitive to many different groups of drugs, and different combinations of drugs are used depending on each specific case.
Quinacrine: Quinacrine, 6-chloro-9-(4-diethylamino-1-methylbutylamino)-2-methoxy-acridine (188.8.131.52), is synthesized from 6,9-dichloro-2-methoxyacridine (184.108.40.206) and aforementioned 4-diethylamino-1-methylbutylamine (220.127.116.11). The 6,9-dichloro-2-methoxyacridine (18.104.22.168) necessary for the synthesis is made in two stages. The initial reaction of 2,4-dichlorobenzoic acid and p-anizidine in the presence of copper dust and potassium carbonate gives 2-(4-methoxyanilino)-4-chlorobenzoic acid (22.214.171.124), which upon reaction with phosphorus oxychloride turns into the necessary 6,9-dichloro-2-methoxyacridine (126.96.36.199) [33-38].
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