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The crystal structure data is reanalyzed for [beta]-hematin and the crystal structure of Plasmodium falciparum hemozoin are solved in order to understand the likely mechanisms of crystal formation and hemozoin reactivity. The studies have shown that two surfaces of the crystal consists of [pi]-[pi] dimers with Fe(III) partly exposed to solvent and capable of undergoing redox reactions.

A novelclass of antimalarial compounds, based on an indol-3-yllinked to the 2-position of a 4-aminoquinoline moiety, shows promisingactivity against the malaria parasite, Plasmodium falciparum. Compounds with a quaternary nitrogen on the quinoline show improvedactivity against the chloroquine-resistant K1 strain. Nonquaternerized4-aminoquinolines retain significant potency but are relatively lessactive against the K1 strain. Alkylation of the 4-amino group preferentiallyimproves the activity against the chloroquine-sensitive 3D7 strain.The quinoline-indoles show only weak activity as inhibitors of β-hematinformation, and their activities are only weakly antagonized by a hemoglobinaseinhibitor. The compounds appear to dissipate mitochondrial potentialas an early event in their antimalarial action and therefore may exerttheir activity by compromising Plasmodiummitochondrial function. Interestingly, we observed a structuralrelationship between our compounds and the anticancer and anthelminthiccompound, pyrvinium pamoate, which has also been proposed to exertits action via compromising mitochondrial function. [ABSTRACT FROM AUTHOR]

We report the synthesis of a series of novel epoxy endoperoxide compounds that can be prepared in high yields in one to three steps from simple starting materials. Some of these compounds inhibit the growth of Plasmodium falciparum in vitro. Structure-activity studies indicate that an endoperoxide ring bisubstituted with saturated cyclic moieties is the pharmacophore. To study the molecular basis of the action of these novel antimalarial compounds, we examined their ability to interact with oxidized and reduced forms of heme. Some of the compounds interact with oxidized heme in a fashion similar to chloroquine and other 4-aminoquinolines, while some of the compounds interact with reduced heme. However, the level of antimalarial potency is not well correlated with these activities, suggesting that some of the endoperoxides may exert their antimalarial activities by a novel mechanism of action.