The chemotherapy of rodent malaria, XXV. Antimalarial activity of WR 122,455 (a 9-phenanthrenemethanol) in vivo and in vitro.

WR 122,455, 3,6-bis-(trifluoromethyl)-alpha-(2-piperidinyl)-9-phenanthrenemethanol HCl, suppresses infection with drug-sensitive Plasmodium berghei N strain in mice. It acts rapidly and affects all the stages of the asexual intraerythrocytic parasites, the effective dose levels being about three times those of chloroquine and one-twelfth to one-fifteenth those of quinine. Under the influence of WR 122,455 haemozoin seems to disappear from the affected parasites following an initial coarsening of the fine pigment granules. These changes are similar to those exerted by quinine. Large doses of WR 122,455 have a residual affect due in part, at least, to deposition of insoluble material in the tissues. The drug appears to exert an antagonistic action on chloroquine when both drugs are administered simultaneously. It has no causal prophylactic effect. In vitro WR 122,455 is a competitive antagonist of chloroquine in a similar manner to quinine, and appears to have a dissociation constant (Ki) of 2-26 x 10(-8) M, making it about 18 times as active as quinine. WR 122,455 interacts strongly with calf thymus DNA, but the mechanism of interaction has yet to be defined. Mice tolerate single doses of a saline/Tween 80 suspensions up to about 400 mg/kg but sc administration induces necrotic changes at the injection site. Up to 30 mg/kg daily po for seven consecutive days is well tolerated systemically but local tissue reaction may occur if the drug is given by the sc or ip routes. However, systemically up to 60 mg/kg is tolerated sc or ip. The relation of WR 122,455 to drug resistant malaria will be reported later.