Folate antagonists. 15. 2,3-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.
Oxidation of an array of 2,4-diamino-6-(arylthio)quinazolines provided the corresponding arylsulfinyl and arylsulfonyl analogues. A variety of these nonclassical analogues of methotrexate exhibited suppressive antimalarial activity superior to that of the parent thioquinazolines against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The sulfinyl- and sulfonylquinazolines also retained antimalarial effects against chloroquine-, cycloguanil-, and DDS-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. Coadministration of one of the most active of these compounds, 2,4-diamino-6-(2-naphthylsulfonyl)-quinazoline (35), with sulfadiazine to monkeys infected with P. falciparum of P. vivax led to greatly enhanced activity and prevented the development of quinazoline resistance.
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis*; D001419:Bacteria / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D002645:Chickens; D004351:Drug Resistance; D005493:Folic Acid Antagonists / Q000138:chemical synthesis*; D000882:Haplorhini; D008288:Malaria / Q000517:prevention & control; D051379:Mice; D010961:Plasmodium; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology
D000962:Antimalarials; D005493:Folic Acid Antagonists; D011799:Quinazolines