ANTI-MALARIAL DRUGS .44. 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 ANTI-METABOLITES WITH PHENOMENAL ANTI-MALARIAL ACTIVIT

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.