Malarial parasites rely on the digestion of hemoglobin during the intra-erythrocytic stage. The enzymatic degradation of hemoglobin yields amino acids for parasite survival, and free heme which is detoxified by conversion to an aggregate of dimeric heme known as hemozoin. Xanthones have been found to subvert this process by formation of soluble drug-heme complexes. We have optimized the simple hydroxyxanthone structure to include side chains with protonatable nitrogen atoms to enhance interaction with the propionate groups of heme and to target the drug to the parasite digestive vacuole. One member of this optimized class of compounds, 3,6-bis-omega-diethylaminoamyloxyxanthone (C5), was used as a prototype for mechanistic studies. By HPLC analysis we demonstrate that the drug accumulates in the digestive vacuole from 5 to approximately 33,000 microM within 1 h of exposure to parasitized red cells. Confocal fluorescence microscopy was used to visualize the accumulation process directly and to document the colocalization of the drug with the acidophilic dye, LysoTracker Red.
Copyright 2002 Elsevier Science B.V.