Kinetic analysis of free radical generation by peroxy, hydroxy, and alkoxy derivatives of 10-dihydroartemisinin

Abstract

Kinetic schemes for the intermolecular oxidation of four analogs of 10-dihydroartemisinin with peroxide substituents were developed. Each step of the kinetic scheme was characterized by the enthalpy, and its activation energy and rate constant were calculated using the model of intersecting parabolas. The antimalarial activity of these derivatives is proved to depend on the number of hydroxyl radicals generated by the compound upon oxidation rather than on the number of peroxide groups. An empirical dependence between the antimalarial efficiency relative to artemisinin (IC₅₀)_rel and the number of generated hydroxyl radicals n_OH was obtained for a series of peroxy, hydroxy, and alkoxy derivatives of 10-dihydroartemisinin (11 compounds): ln(IC₅₀)_rel =–13.51 + 3.76•n_OH.