Floxacrine analog WR 243251 inhibits hematin polymerization

Floxacrine was a promising antimalarial compound that led to the identifica tion of WR 243251. On the basis of their structures, we suspected that thes e compounds might be good inhibitors of hematin polymerization. Indeed, WR 243251 was as potent and floxacrine was only 2-fold less potent than chloro quine as inhibitors of this process. However. this hematin polymerization i nhibition did not completely account for the increased antimalarial potency of WR 243251 versus chloroquine. The WR 243251 ketone hydrolysis product W R 243246 was without activity against hematin polymerization. These data al so confirm that hematin polymerization inhibition can be quite sensitive to small changes in inhibitor structure.