Synthesis and Antimalarial Assessment of a New Series of Orally Active Amino-Functionalized Spiro 1,2,4-Trioxanes

Keto-trioxanes 7a-d, easily accessible in two steps from allylic alcohols 5a-d, underwent reductive amination with substituted anilines to furnish amino-functionalized trioxanes 8a-i, 9a-i, 10a-i, and 11a-i. All these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice. 2-Naphthalene-based trioxanes 9c and 9i, the most active compounds of the series, provided 100% protection to the malaria-infected mice at 24 mg/kg x 4 days, while the related trioxane 9b and phenanthrene-based trioxane 11e provided a similar level of protection at 48 mg/kg x 4 days. All other trioxanes, except 10c, 10d, and 10g, provided 100% protection at 96 mg/kg x 4 days. In this model, beta-arteether provided 100% protection at 48 mg/kg x 4 days and 20% protection at 24 mg/kg x 4 days.