Synthesis and Antimalarial Activity of 3,3-Spiroanellated 5,6-Disubstituted 1,2,4-Trioxanes

Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg x 4 days to 24 mg/kg x 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg x 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, beta-arteether provided 100 and 20% protection at 48 mg/kg x 4 days and 24 mg/kg x 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug beta-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.