New Adamantane-Based Spiro 1,2,4-Trioxanes Orally Effective against Rodent and Simian Malaria

New 6-arylvinyl- and 6-adamantylvinyl-substituted 1,2,4-trioxanes (13ag and 14a,b) have been prepared and evaluated for antimalarial activity against multidrug resistant Plasmodium yoelii nigeriensis in mice by both oral and intramuscular routes. While all the 6-arylvinyl-substituted trioxanes, 13af, showed promising activity, none of the 6-adamantylvinyl-substituted trioxanes, 13g and 14a,b, exhibited significant activity. Trioxane, 13f, the most active compound of the series, provided 100% and 80% protection to malaria-infected mice at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. In this model, β-arteether (3) provided 100% protection at 48 mg/kg × 4 days and only 20% protection at 24 mg/kg × 4 days. Trioxane 13f also showed complete suppression of parasitaemia at 10 mg/kg × 4 days by oral route in rhesus monkeys infected with P. cynomolgi. None of these trioxanes, except 13f, showed significant activity by the intramuscular route.