Xanthones as antimalarial agents: Stage specificity

The erythrocytic development of Plasmodium falciparum is divided into the r ing, trophozoite, and schizont stages based on morphologic assessment. Usin g highly synchronous ring and trophozoite cultures of P. falciparum, we obs erved considerable differences in their sensitivity to hydroxyxanthones: tr ophozoites were much more sensitive to the drugs than ring-stage parasites. Trophozoites treated with a prototypic xanthone, the 2,3,4,5,6-pentahydrox y derivative (X5), were arrested in their development and became degenerate in appearance within 24 hr of drug exposure. These morphologic changes app eared to reflect the cytotoxic nature of the action of the drug against the parasite, since daughter ring-stage forms were not observed following addi tion of the drug. That X5 was more active against parasites in the later st ages of intraerythrocytic development is consistent with the proposed mode of action, inhibition of heme polymerization. Knowledge of the structure-ac tivity relationships for xanthones as antimalarial agents has also been exp anded. Xanthones with a hydroxyl group in the peri-position exhibited decre ased antimalarial activity, possibly due to intramolecular hydrogen bonding with the carbonyl and consequent reduced affinity for heme. Paired hydroxy ls attached to the lower half of the xanthone greatly enhanced drug potency .