Antimalarial drugs. 39. Folate antagonists. 13. 2,4-Diamino-6-[(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)thio]quinazoline and related 2,4-diamino-6-[(phenyl- and naphthyl)thio]quinazolines, a unique class of antimetabolites with extraordinary antimalarial and antibacterial effects
An array of nonclassical thioquinazoline analogs of methotrexate was prepared by cyclization of the requisite 2-amino-5-(arylthio)benzonitrile with chloroformamidine hydrochloride (28-79%). The aminonitrile precursors were obtained by SnCl2-HCl reduction (28-99%) of the corresponding 2-nitro-5-(arylthio)benzonitriles, which were synthesized by the condensation of the appropriate 5-chloro-2-nitrobenzonitriles with various arylthiols (36-83%). Many of the thioquinazolines showed suppressive antimalarial activity comparable with or superior to chloroquine, cycloguanil and pyrimethamine against drug-sensitive lines of Plasmodium berghei in mice and P. gallinaceum in chicks, and several displayed potent prophylactic activity against P. gallinaceum. The thioquinazolines retained potent antimalarial effects against chloroquine-, cycloguanil-, pyrimethamine- and dapsone-resistant lines of P. berghei in mice and against chloroquine- and pyrimethamine-resistant strains of P. falciparum in owl monkeys. The most active compound, 2,4-diamino-6-[(.alpha.,.alpha.,.alpha.-trifluoro-m-tolyl)thio]quinazoline, was designated for preclinical toxicological studies. Numerous substances exhibited in vitro activity against a broad spectrum of pathogenic bacteria at concentrations of < 0.25 .mu.g/ml. The thioquinazolines also were potent folate antagonists, causing 50% inhibition of Streptococcus faecalis R (ATCC 8043) at drug concentrations ranging from 0.2-2.0 ng/ml. Structure-activity relationships are discussed.