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 (DU1302c), prepared from alpha-terpinene, a cheap natural product, showed efficient antimalarial activity in vitro on both sensitive and resistant strains of Plasmodium falciparum (lC(50)=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).