New orally active derivatives of artemisinin with high efficacy against multidrug-resistant malaria in mice

A new series of ether derivatives of dihydroartemisinin have been prepared and evaluated for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in mice by oral route. These new derivatives 7-17 are highly lipophilic ( log P in the range of 5.51 to 7.19) as compared with beta-arteether (log P 3.84), and several of them are two- to four-fold more active than beta-arteether. Among the ether derivatives, R-isomers are more active than the beta- isomers. The ether derivatives 12 alpha and 14 alpha, the most active compounds of the series, provided 100% protection to infected mice at 12 mg/kg x 4 days. In this model,- arteether provides 100% and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively.