An endoperoxide-based hybrid approach to deliver falcipain inhibitors inside malaria parasites.

The emergence of artemisinin-resistant Plasmodium falciparum malaria in Southeast Asia has reinforced the urgent need to discover novel chemotherapeutic strategies to treat and control malaria. To address this problem, we prepared a set of dual-acting tetraoxane-based hybrid molecules designed to deliver a falcipain-2 (FP-2) inhibitor upon activation by iron(II) in the parasite digestive vacuole. These hybrids are active in the low nanomolar range against chloroquine-sensitive and chloroquine-resistant P. falciparum strains. We also demonstrate that in the presence of FeBr₂ or within infected red blood cells, these molecules fragment to release falcipain inhibitors with nanomolar protease inhibitory activity. Molecular docking studies were performed to better understand the molecular interactions established between the tetraoxane-based hybrids and the cysteine protease binding pocket residues. Our results further indicate that the intrinsic activity of the tetraoxane partner compound can be masked, suggesting that a tetraoxane-based delivery system offers the potential to attenuate the off-target effects of known drugs.