New Adamantane-Based Spiro 1,2,4-Trioxanes Orally Effective against Rodent and Simian Malaria<sup>†</sup>

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