Synthesis and Antimalarial Activity of Trioxaquine Derivatives

Trioxaquines are dual molecules that contain a trioxane motif linked to an aminoquinoline entity. Among the different compounds of this series, trioxaquine cis‐15 (DU1302 c), prepared from α‐terpinene, a cheap natural product, showed efficient antimalarial activity in vitro on both sensitive and resistant strains of Plasmodium falciparum (IC50=5–19 nM). A stereochemical description of this stable, nontoxic, and non‐genotoxic antimalarial agent is detailed. Mice infected with P. vinckei were successfully treated with cis‐15 in a four‐day suppressive test. The doses required to decrease parasitemia by 50 % (ED50) were 5 and 18 mg kg−1 d−1 after intraperitoneal and oral administration, respectively. Parasitemia clearance was complete without recrudescence at an intraperitoneal dose of 20 mg kg−1 d−1. A stable, nontoxic, and non‐genotoxic antimalarial agent, compound 1 (DU1302 c), is a trioxaquine that was prepared from α‐terpinene. It exhibited high antimalarial activity in vitro against Plasmodium falciparum, as well as in vivo activity after being orally administered to infected mice.