Antimalarial activity of floxacrine (HOE 991) II: Studies on causal prophylactic and blood schizontocidal action of floxacrine and related dihydroacridinediones against Plasmodium yoelii and P. berghei

Abstract

The causal prophylactic and blood schizontocidal action of six dihydroacridinediones were assessed in mice using the Plasmodium yoelii 17X strain in sporozoite-induced infections and the P. berghei K 173 strain in blood-induced infections respectively. A remarkable relationship was shown between the action on pre-erythrocytic forms and on blood forms of malaria parasites. A trifluoromethyl group in the para (4—) position of the 3-phenyl ring of the 7-chloro-10-hydroxy-3,4-dihydroacridine-1,9-(2H,10H)-dione (compound Hoe 991: floxacrine) proved the most favourable substituent of a group of electronegative substituents concerning antimalarial activity. The CPD₅₀/CD₅₀ of Hoe 991 against pre-erythrocytic/blood forms of P.yoelii/P. berghei was 0·37 mg kg⁻¹ (X 1)/1·7 mg kg⁻¹ (X5) after the intraperitoneal (ip)/subcutaneous (sc) route. As demonstrated by compound Hoe 990 double substitution in the 3-phenyl ring with 2-chloro-, 4-trifluoromethyl- caused a marked residual action. The causal prophylactic effect (CPD₅₀) of dihydroacridinediones tested was superior to that of primaquine but inferior to that of pyrimethamine, whereas floxacrine revealed a similar effect to pyrimethamine at the CPD₉₅ level. Serious side effects in subacute toxicity tests in rats and dogs, such as dose-dependent chronic periarteritis and a bleeding tendency, led to termination of advanced preclinical investigations of floxacrine (Hoe 991).