XANTHONES AS ANTIMALARIAL AGENTS - STUDIES OF A POSSIBLE MODE OF ACTION

We recently demonstrated that 2,3,4,5,6-pentahydroxyxanthone (X5) inhi bits the in vitro growth of both chloroquine-sensitive and multidrug-r esistant strains of P. falciparum. To study the molecular basis of its antimalarial action, we tested X5 and selected hydroxyxanthone analog s as inhibitors of in vitro heme polymerization in a low ionic strengt h phosphate solution at mildly acidic pH, We found that addition of 1 Eq. of X5 resulted in complete inhibition of polymerization in this sy stem whereas addition of up to 40 Eqs. of standard antimalarial compou nds (chloroquine, primaquine, quinacrine, artemisinin and methylene bl ue) had no such effect although these compounds did co-precipitate wit h heme. The antimalarial potency of the hydroxyxanthones correlated we ll with their ability to inhibit in vitro heme polymerization in our a ssay, suggesting that these compounds exert their antimalarial action by preventing hemozoin formation, Based on the observed structure-acti vity relationships, we propose a model displaying possible interaction s between hydroxyxanthones and heme. (C) 1997 Federation of European B iochemical Societies.