Quantum chemical study of the intermediate complex required for iron-mediated reactivity and antimalarial activity of dispiro-1,2,4-trioxolanes

Quantum chemical methods were used to obtain a structure for the peroxide–iron intermediate complex required for the inner-sphere reduction of dispiro-1,2,4-trioxolane antimalarials. Investigation of this biologically important interaction with iron(II) allows further understanding of the mechanisms of action and clearance of this promising new class of fully synthetic peroxide antimalarials. UHF, B3LYP and B3LYP//MP2 calculations were undertaken to provide structural and energetic information about the coordination complex of iron(II) with five representative trioxolanes, ranging in both iron-mediated reactivity and antimalarial activity. Significant energy differences were observed between the conformational isomers of these trioxolanes, indicating the importance of steric interactions between the iron complex ligands and the trioxolane substituents. These calculations may explain the slower iron-mediated reaction rates of trioxolanes that preferentially adopt a conformation that sterically shields the peroxide bond. The relationship between antimalarial activity and accessibility of the peroxide bond to iron has also been demonstrated for these trioxolanes.