Development of Hypoestoxide for use in treatment and prevention of Malaria

• Hypoestoxide is effective in vitro and in vivo against murine blood and liver stages (in vitro) of malaria parasites.


• Hypoestoxide is orally active at very low doses in vivo against murine malaria parasites. Hypoestoxide is non-toxic (MTD > 750 mg/kg in mice).


• The mechanism of action is presently unknown, but its ability to depolymerize actin and inhibit cell migration may be related to its ability to inhibit sporozoite motility/migration as has been shown with Cytochalasin-D in vitro. Sporozoites need to migrate through and within cells/traverse several cells to activate signaling pathways necessary for entering and further development in hepatocytes or to search for specific hepatocytes that are suitable for infection. For the blood stage, the alpha/beta-unsaturated ketone moiety on hypoestoxide offers the possibility that it may interfere with mitochondrial electron transport in the parasite as has been shown with beta-methoxyacrylates. Another possible mechanism is lowering of glutathione levels in the parasite by either direct scavenging (HE conjugates easily with glutathione as evidenced by one of its metabolites) and/or by inhibiting the enzymes involved in glutathione synthesis and recycling.