First computational evidence of a competitive stepwise and concerted mechanism for the reduction of antimalarial endoperoxides.
We study structural analogues of endoperoxides belonging to the family of G factors which present moderate to good antimalarial activity. Their biological activity is related to the reduction and cleavage of the O-O bond. Generally, the O-O bond reduction of model endoperoxides, as well as artemisinin, occurs by a concerted dissociative electron transfer (ET) mechanism. For the G3 and G3Me compounds, the experimental counterpart indicates an unexpected competition between a concerted and a stepwise mechanism, but no intermediate species can be isolated. We thus perform DFT studies on the reduction of G3 and G3Me compounds. We confirm the formation of an intermediate radical anion followed by cleavage of the O-O bond in a second step. We characterize the stable conformations for the radical anions G(3)(*-) and G(3)Me(*-) resulting from the ET and the associated reaction pathway. We also calculate the reorganization energy upon ET in relation to the Marcus theory using the DFT method. These results provide valuable insight into understanding the biological activity of G-factor endoperoxides as potential therapeutic antimalarial agents.
Lacaze-Dufaure
Corinne
C
Centre Interuniversitaire de Recherche et d'Ingénierie des Matériaux, CNRS UMR 5085, ENSIACET, Toulouse, France. corinne.dufaure@ensiacet.fr
Najjar
Fadia
F
André-Barrès
Christiane
C
D000962:Antimalarials / Q000737:chemistry*; D037621:Artemisinins / Q000737:chemistry; D004579:Electron Transport; D008962:Models, Theoretical; D010084:Oxidation-Reduction; D010545:Peroxides / Q000737:chemistry*; D011789:Quantum Theory
D000962:Antimalarials; D037621:Artemisinins; D010545:Peroxides; C031327:artemisinin