Synthesis and Antimalarial Activities of New Hybrid Atokel Molecules

The currently spreading resistance of the malaria parasite Plasmodium falciparum to artemisinin‐based combination therapies makes an urgent need for new efficient drugs. Aiming to kill artemisinin‐resistant Plasmodium, a series of novel hybrid drugs named Atokels were synthesized and characterized. Atokels are based on an 8‐amino‐ or 8‐hydroxyquinoline entity covalently bound to a 1,4‐naphthoquinone through a polyamine linker. These drugs have been designed to target the parasite mitochondrion by their naphthoquinone moiety reminiscent of the antimalarial drug atovaquone, and to trigger a damaging oxidative stress due to their ability to chelate metal ions in order to generate redox active complexes in situ. The most effective Atokel drug shown a promising antimalarial activity (IC(50)=622 nm on an artemisinin‐resistant P. falciparum strain) and no cytotoxicity at 50 μm indicating a specific antiplasmodial mode of action.