Antimalarial activity of Floxacrine (HOE 991) I. Studies on blood schizontocidal action of Floxacrine against Plasmodium berghei, P. vinckei and P. cynomolgi.

Floxacrine (HOE 991), 7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)3,4-dihydroacridine-1,9-(2H, 10H) dion, shows a high level of antimalarial action against blood-induced infection of drug-sensitive and drug-resistant lines of Plasmodium berghei in mice, rats and Syrian hamsters. The drug is also a potent blood schizontocide against drug-sensitive P. vinckei strains in rodents and P. cynomolgi in rhesus monkeys. The CD50/CD90 values against the drug-sensitive P. berghei strain ascertained in the '28-day test' in mice were 4.3/6.7 mg/kg after the oral route and 1.7/3.6 mg/kg after the subcutaneous (sc) route. In the 'two- and four-day test' the ED50 against sensitive P. vinckei was 0.7 mg/kg in both mice and rats. A moderate prophylactic effect could be demonstrated after the sc route probably due to a 'depot effect' of the water-insoluble active principle. Floxacrine was also highly active against P. berghei-lines which were resistant to chloroquine, mepacrine, dihydrofolate reductase inhibitors, sulfadoxine and dapsone. Resistance to HOE 991 could be developed in P. berghei and P. cynomolgi when the compound was used alone and administered repeatedly in subcurative doses. The antimalarial activity of the compound was not influenced by p-aminobenzoic acid or folic acid supplements in diets. Structural changes induced by floxacrine on pigment cytoplasm and nucleus in erythrocytic stages of P. berghei differed in some aspects from those of mepacrine and chloroquine. It is therefore assumed that the mode of action of floxacrine differs from that of the known antimalarial drugs. The general tolerance of the compound in rodents and rhesus monkeys is good and there is a wide range between the effective and maximum tolerated doses. Floxacrine was also effective at 100 ppm against pathogen Eimeria species in chickens, at 1000 mg/kg orally against Fasciola hepatica in rats and at 300-800 mg/kg orally against Heterakis spumosa in rats.