New orally active amino- and hydroxy-functionalized 11-azaartemisinins and their derivatives with high order of antimalarial activity against multidrug-resistant Plasmodium yoelii in Swiss mice.

By use of artemisinin 1 as the starting material, two new amino- and hydroxy-functionalized 11-azaartemisinins 9 and 11 and their derivatives 12a-g, 13a-g, 14a-g, and 15a-c have been prepared and screened for antimalarial activity by oral route against multidrug-resistant Plasmodium yoelii in Swiss mice. While azaartemisinins 9 and 11 showed only modest activity, several of their derivatives showed high order of antimalarial activity. Biphenyl-based compound 13f, the most active compound of the series, provided 100% and 80% protection to the infected mice at 12 mg/kg × 4 days and 6 mg/kg × 4 days, respectively. Compounds 12f, 13b, 13e, 13g, and 14f showed 100% protection at 12 mg/kg × 4 days, while compounds 12a-c, 14a, 14c-e, 14g, and 15a-c showed similar levels of protection at 24 mg/kg × 4 days. Clinically useful drug β-arteether provided 100% protection at 48 mg/kg × 4 days and 20% protection at 24 mg/kg × 4 days in this model.