The promise of synthetic 1,2,4 trioxolane antimalarials as potential successors to current frontline artemisinin derivatives has been hampered by limited solubility and poor pharmacol. properties of second-generation analogs.OZ439, the most developed synthetic endoperoxide antimalarial to date, is of limited clin. utility due to solubility issues that result in colloid formation and poor bioavailabity.Herein we report TTR-008, a synthetic 1,2,4 trioxolane with greatly improved aqueous solubility and metabolic stability comparative to OZ439 and with retained antiparasitic effect.TTR-008 demonstrated low nanomolar potency in in vitro testing against P. falciparum and achieved single-dose cures in the rodent P. berghei model of malaria.Addnl., TTR-008 completely eliminated parasitemia in K13 C580Y mutant parasites in the Ring Stage Assay, an effect not observed with OZ439.Effectiveness against K13 mutant parasites is potentially attributable to the steric bulk of the 3' substituent on the endoperoxide-adjacent cyclohexyl ring of TTR-008, which disfavors the iron-reactive conformer of the scaffold and results in increased compound half-life in the presence of ferrous iron as observed directly in an iron fragmentation assay.Taken together these results indicate TTR-008 may be a promising candidate for addnl. preclin. evaluation and suggest further exploration of the 3' position for addnl. analog development.