Antimalarial Properties of Floxacrine, a Dihydroacridinedione Derivative

Abstract

Evaluations of the activities of floxacrine [7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)-3,4-dihydroacridine-1,9(2H, 10H)-dione] in owl monkeys infected with trophozoites of a chloroquine-quinine-resistant strain of Plasmodium falciparum, a strain of this plasmodium resistant to both of these quinolines and pyrnmethamine, or a strain of P. vivax resistant only to pyrimethamine showed that: (i) this compound regularly effected temporary clearance of parasitemia at daily doses of 1.25 to 2.5 mg/kg; (ii) doses required for the cure of established infections were larger by factors of 6 to 64 than those that effected parasite clearance; (iii) there was more than a 10-fold difference in doses required for the cure of infections with the different strains; and (iv) resistance to floxacrine developed rapidly. Evaluations of the activities of floxacrine in rhesus monkeys challenged with sporozoites of P. cynomolgi showed that: (i) 0.625-mg/kg doses administered daily throughout the incubation period provided complete protection against infection; (ii) single 40.0-mg/kg doses delivered 2 h before sporozoite challenge were without prophylactic activity; and (iii) daily doses of 40.0 mg/kg, the maximum tolerated level, productive of a hemorrhagic syndrome in some subjects, would not cure established infections. These observations suggest that the potential contribution of floxacrine to malaria therapy would be limited to the prophylactic area and for practical reasons would be restricted there by the requirement for daily dosage.Floxacrine (Fig. 1) identical doses of this dihydroacridinedione derivative were required for the cure of infections with the drug-susceptible strain and strains resistadnt to chloroquine, pyrimethamine, and sulfadoxine; (iii) floxacrine was approximately twice as active when administered subcutaneously as when delivered orally; and (iv) irrespective of route of administration, the compound had a favorable therapeutic index; i.e., the ratio of the 50% lethal dose to the dose required to cure 50% of infections (LD5o/CD5o) was in excess

Acridinediones: Selective and Potent Inhibitors of the Malaria Parasite Mitochondrialbc1Complex

“…1) Fink, 1979, 1982;Schmidt, 1979;Kesten et al, 1992;Dorn et al, 2001). Both of these compounds show heme binding and bc 1 inhibitory properties; however, whereas floxacrine kills parasites via a heme-mediated process, WR249685 is shown here to be a highly selective inhibitor of the Q o of the Plasmodium falciparum bc 1 complex.…”

Enhancement of the curative activity of primaquine by concomitant administration of mirincamycin

“…There are at least two available agents in addition to mirincamycin that merit such evaluation. They are (i) RC-12 [1,2-dimethoxy-4-(bisdiethylaminoethyl)-amino-5-bromobenzene], which has highly reproducible prophylactic and radical curative activity against infections with P. cynomolgi in rhesus monkeys (22; personal observations to be published) and has been evaluated only superficially against infections with P. vivax in humans (4), and (ii) floxacrine [7-chloro-10-hydroxy-3-(4-trifluoromethylphenyl)-3 ,4-dihydroacridine-1 ,9-(2H,1OH)-dione], which has a substantial capacity to prevent P. cynomolgi infections, although limited capacities for cure (13).…”

New Antiamebic Acridines

“…Acridanones have been reported to possess a variety of biological activities, notably antimalarial, for example floxacrine [1][2][3][4], but also anthelminthic [5] and trypanocidal [6]. The mechanism of bio logical action of the related 9-aminoacridines is thought to be by intercalation of the molecule into the DNA helix [7,8].…”