The structure of antimalarial dispiro-1,2,4-trioxolanes: A density functional approach

Ab initio DF/B3-LYP/cc-pVDZ calculations have been performed on three dispiro-1,2,4-trioxolane systems (2)–(4). Interest in these systems comes from the fact that a water-soluble derivative of (3), known as OZ277, has been synthesized and identified as antimalarial drug with activity superior to those of semisynthetic artemisinins. Structural data have been obtained regarding the atomic arrangement around the peroxide bond for the three systems. Making reference to (3), two conformers have been calculated depending on the axial or equatorial bond of spirocyclohexane with the peroxide oxygen of 1,2,4-trioxolane. In particular, while the peroxide oxygen on the spiroadamantane side is sterically hindered for both the axial and the equatorial conformer, the peroxide oxygen on the spirocyclohexane side is more accessible to external attack when the conformer is axial than when is equatorial.