Reduction of the Double Bond of 6-Arylvinyl-1,2,4-trioxanes Leads to a Remarkable Increase in Their Antimalarial Activity against Multidrug-Resistant Plasmodium yoelii nigeriensis in a Swiss Mice Model

Novel 6-arylethyl-1,2,4-trioxanes6a-i and 7a-i are easily accessible in one step from the diimide reduction of 6-arylvinyl-1,2,4-trioxanes 5a-i. All of these new trioxanes were assessed for their oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in a Swiss mice model. Most of the saturated trioxanes 6c, 6f, 6g, 6h, and 6i, the active compounds of the series, provided 100% protection to the malaria-infected mice at a dose of 24 mg/kg x 4 days. Further, trioxane 6i, the most active compound of the series, also showed 100% protection even at a dose of 12 mg/kg x 4 days and 20% protection at a dose of 6 mg/kg x 4 days. In this model, beta-arteether provided 100% protection at a dose of 48 mg/kg x 4 days and only 20% protection at a dose of 24 mg/kg x 4 days via the oral route, which was found to exhibit 4-fold antimalarial activity compared with the currently used drug beta-arteether.

Automated summary

The newly synthesized trioxane compounds showed good oral antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis, with the most active compound providing 100% protection to infected mice.