Antimalarial drugs. 46. Folate antagonists. 15. 2,4-Diamino-6-(2-naphthylsulfonyl)quinazoline and related 2,4-diamino-6-[(phenyl and naphthyl)sulfinyl and sulfonyl]quinazolines, a potent new class of antimetabolites with phenomenal antimalarial activity

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Abstract
Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogs. A variety of these nonclassical analogs of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium bergei in mice and P. gallinaceum in chicks, and several displayed prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine and cycloguanil-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of 1 of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline, with sulfadiazine to monkeys infected with P. falciparum or P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.