Novel, potent, semisynthetic antimalarial carba analogues of the first-generation 1,2,4-trioxane artemether

Ten novel, second-generation, fluorinated ether and ester analogues of the potent first-generation analogues artemether (4a) and arteether (4b) have b een designed and synthesized. All of the compounds demonstrate high antimal arial potency in vitro against the chloroquine-sensitive HB3 and -resistant K1 strains of Plasmodium falciparum. The most potent derivative 8 was 15 t imes more potent than artemisinin (2) against the HB3 strain of P. falcipar um. In vivo, versus Plasmodium berghei in the mouse, selected derivatives w ere generally less potent than dihydroartemisinin with ED50 values of betwe en 5 and 8 mg/kg. On the basis of the products obtained from the in vitro b iomimetic Fe(II)-mediated decomposition of 8, the radical mediator of biolo gical activity of this series may be different from that of the parent drug , artemisinin (2).