A Fragmenting Hybrid Approach for Targeted Delivery of Multiple Therapeutic Agents to the Malaria Parasite

Hybrid drugs with a twist: The coupling of iron(II)‐promoted trioxolane ring scission with a β‐elimination reaction enables the targeted delivery of multiple drug activities to the malaria parasite. A prototypical fragmenting hybrid (shown) comprises an iron(II)‐reactive 1,2,4‐trioxolane ring (red) joined via a masked retro‐Michael linker (blue) to a partner drug—in this case a protease inhibitor (green). Successful delivery of the protease inhibitor to intra‐erythrocytic Plasmodium falciparum parasites is demonstrated using a chemical–biological approach.