Over 700 causal prophylactic and radical curative
antimalarial drugs have been discovered during the screening of approximately 4000 chemical compounds in rodent and simian
malaria models. Causal prophylactic activity in the Plasmodium berghei-rodent model was demonstrated by 10 distinct groups of chemicals: 1)
tetrahydrofolate dehydrogenase inhibitors, 2)
naphthoquinones, 3) dihydroacridinediones, 4)
tetrahydrofurans, 5) guanylhydrazones, 6) analogues of
clopidol, 7)
quinoline esters, 8) dibenzyltetrahydro-
pyrimidines, 9) 6-
aminoquinolines, 10) 8-
aminoquinolines.Of the causal prophylactic compounds, only the 6- and 8-
aminoquinolines were capable of curing persistent exoerythrocytic
infections of P. cynomolgi in rhesus monkeys. The 6-
aminoquinolines were substantially less active than
primaquine.This report describes a series of 4-methyl-5-phenoxy-6-methoxy-8-
aminoquinolines, which are potent blood schizontocides and radical curative drugs. The most active member of this series, 4-methyl-5-(3-trifluoromethylphenoxy)-6-methoxy-8-[(4-amino-1-methylbutyl)| amino]
quinoline succinate (
WR 225448), was 5 times more active than
primaquine in curing persistent exoerythrocytic
infections of P. cynomolgi in rhesus monkeys.As a blood schizontocide,
WR 225448 was effective in animal models against P. berghei, P. cynomolgi, P. vivax, and both
drug-sensitive and
drug-resistant strains of P. falciparum.
WR 225448 was also more toxic than
primaquine in rats on subacute (28-day) administration.