Spiro and Dispiro-1,2,4-trioxolanes as Antimalarial Peroxides: Charting a Workable Structure−Activity Relationship Using Simple Prototypes

This paper describes the discovery of synthetic 1,2,4-trioxolane antimalarials and how we
established a workable structure−activity relationship in the context of physicochemical,
biopharmaceutical, and toxicological profiling. An achiral dispiro-1,2,4-trioxolane (3) in which
the trioxolane is flanked by a spiroadamantane and spirocyclohexane was rapidly identified
as a lead compound. Nonperoxidic 1,3-dioxolane isosteres of 3 were inactive as were trioxolanes
without the spiroadamantane. The trioxolanes were substantially less effective in a standard
oral suspension formulation compared to a solubilizing formulation and were more active when
administered subcutaneously than orally, both of which suggest substantial biopharmaceutical
liabilities. Nonetheless, despite their limited oral bioavailability, the more lipophilic trioxolanes
generally had better oral activity than their more polar counterparts. In pharmacokinetic
experiments, four trioxolanes had high plasma clearance values, suggesting a potential
metabolic instability. The toxicological profiles of two trioxolanes were comparable to that of
artesunate.