ANTIMALARIAL ACTIVITY OF WR-243251, A DIHYDROACRIDINEDIONE

WR 243251 is a dihydroacridinedione that was evaluated for antimalaria l blood schizonticidal activity in vitro and in vivo. The in vitro dos es calculated to kill 50% of organisms were 11 nM for a chloroquine-su sceptible, mefloquine-resistant standard strain and 25 nM for a chloro quine- and pyrimethamine-resistant standard strain. The total dose nee ded to cure 100% of mice infected with a drug-susceptible strain of Pl asmodium berghei was 12 to 20 mg/kg of body weight for both oral and s ubcutaneous administration. The regimen needed to cure 100% of Aotus m onkeys infected with Plasmodium falciparum was 8 mg/kg/day for 3 days (chloroquine-susceptible strain) and 16 mg/kg/day for 3 days (chloroqu ine-resistant strain). The 100% curative doses for Aotus monkeys did n ot increase for parasites previously exposed to subcurative doses. The absolute value of the curative doses of WR 243251 was comparable to o r lower than the values for clinical antimalarial agents. The high abs olute activity, comparability of activities against susceptible and re sistant parasites, and inability to induce resistance by exposure to s ubcurative doses suggest that WR 243251 has strong potential as a bloo d schizonticidal agent.