Elucidation of the action mechanism of new antimalarial endoperoxides: a dft investigation to support drug design. 3D-Structure Activity Relationships of new simple antimalarial endoperoxides.

Malaria is a global health threat for about 40% of the world population, mainly located in the tropical and subtropical areas where every thirty seconds a child affected by this disease is destined to die. The therapeutic choices are still too limited for the large and poor malaria market and there is an urgent need of new and economically affordable antimalarial drugs. In this context, through a multidisciplinary approach, we designed new antimalarials based on the dioxane scaffold of plakortin (1). As the mechanism of action of antimalarial endoperoxides is not well understood yet, we performed a density functional study aiming to elucidate thermodynamic and kinetic features of our new lead compound 3 compared to reference compounds plakortin (1) and artemisinin (2). In details, the possibility of the dissociative electron transfer induced by Fe(II)-heme in the first step of the process was verified through the theoretical evaluation of the antimalarial redox potential E°. The combination of density functional theory and polarizable continuum model (PCM) of the solvent assures to obtain E° reliable values [1] against the demonstrated limits of usual experimental procedures [2]. Besides, to validate the through-space H-shift mechanism of action hypothesized in our previous studies [3], we identified the molecular species involved in the process with the aim to trace the reaction pathway. With this purpose, a DFT investigation of pre-reactive complexes, transition states and radical intermediates was performed considering all the coordination modes of iron to the endoperoxide function and different spin states of the metal.