Synthesis and Antimalarial Activity of Trioxaquine Derivatives

Abstract

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.