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 Mice1

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Abstract
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.

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