Antimalarial activity and metabolism of dihydroartemisinin-derived dimer

The dihydroartemisinin-derived dimer (DHA dimer) was synthesized, and its antimalarial activities were evaluated both in vitro and in vivo. The dimer IC₅₀ value of 0.51 ± 0.12 nM in vitro was significantly lower than that of DHA at 1.81 ± 0.70 nM. The dimer ED₅₀ values were 0.44 ± 0.03 and 0.18 ± 0.03 mg/(kg·day) in vivo for intragastric (i.g.) and intravenous (i.v.) groups, respectively, to Plasmodium yoelii rodent malaria. It also performed better relative to those of DHA which had ED₅₀ values of 0.76 ± 0.03 mg/(kg·day) (i.g.) and 0.32 ± 0.03 mg/(kg·day) (i.v.). Moreover, the recrudescence rate, negative conversion rate, and cure rate of the dimer showed superior performance. Furthermore, the metabolites and major metabolic pathways of the dimer in rats were preliminarily investigated using the HPLC-HRMSⁿ method. Twenty-seven metabolites, including DHA, 11 metabolites of DHA, and 15 other novel metabolites, were detected in rats after i.g. administration of dimer. The metabolic pathways of the 15 novel metabolites were inferred: deoxygenation, hydroxylation, and hydroxylation with dehydration.