The Antimalarial Activity of Metachloridine (2-Metanilamido-5-Chloropyrimidine) and Other Metanilamide Derivatives in Test Infections with Plasmodium gallinaceum

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Abstract
The relative antimalarial activities of metanilamide (meta-aminobenzenesulfonamide) and 42 of its derivatives have been detd. using sporozoite- and blood-induced infections of P. gallinaceum in the chicken. The most active members of the series, 2-metanilamido-5-chloro-pyrimidine (metachloridine) and its bromine and iodine analogues, are 16 or more times as active as quinine or sulfadiazine on a dosage basis. Sporozoite-induced infections are prevented by as little as 5-10 mg. of metachloridine/kg./day administered 2 days before and 8 days after inoculation; with the same schedule, 0.2 mg./kg./day prolongs the incubation period markedly. Blood-induced infections are suppressed by 2 mg./kg./day. The lower doses result in blood levels of 0.2 mg./100 ml. or less. The maximum tolerated dose in chickens is over 1 gm./kg./day (blood levels of about 30 mg./lOO ml.). This gives a very wide margin of safety between effective and toxic doses. Rats, dogs, and monkeys tolerated blood cones. of 6 to 30 mg./lOO ml. for long periods without evidences of toxicity. Even with max. tolerated doses, established infections of P. gallinaceum are not eradicated. The metanilamides probably do not act by the same mechanism as the sulfanilamides since they are not readily antagonized by p-aminobenzoic acid, and are ineffective against several species of bacteria as well as the coccidian, Eimeria tenella, which are sensitive to sulfanilamides. They are also highly active against P. cathemerium which is relatively insensitive to sulfanilamides. The most active members of the metanilamide series are those with N1-pyrimidine substituents. With the exception of halogenation in the 5-position of the pyrimidine ring, other modifications of 2-metanilamidopyrimidine have not enhanced activity. Metachloridine at high blood cones, is not active against Trypano-soma equiperdum, T. cruzi, Leishmania donovani or Schisto-soma mansoni in vivo.

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