Antimalarial Bicyclic Peroxides Belonging to the G-Factor Family: Mechanistic Aspects of their Formation and Iron (II) Induced Reduction

Jérémy Ruiz (1) , Joëlle Azéma (2) , Corinne Payrastre (2) , Michel Baltas (2) , Beátrice Tuccio (3) , Henri Vial (4) , Christiane André-Barrès (2)

1 LMBP - Laboratoire de Mathématiques Blaise Pascal
2 SPCMIB - Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique
3 ICR - Institut de Chimie Radicalaire
4 DIMNP - Dynamique des interactions membranaires normales et pathologiques

Artemisinin and its derivatives are peroxide-containing compounds targeting P. falciparum. We review here structural analogues of bicyclic peroxides belonging to the G factors family presenting antimalarial properties. They were synthesised under Mannich type conditions, followed by an autoxidation step resulting exclusively in the peroxide. As the electron transfer from haem or free iron to the peroxide is the first step in the mode of action of artemisinin-like compounds , the redox properties of some endoperoxides were studied by electrochemistry allowing the evaluation of the reduction standard potentials. The Fe(II) induced reduction was also investigated and the reactivity of the C-centered radical intermediate formed was linked to the antimalarial activity. These bicyclic peroxides both with various hybrid molecules containing the endoperoxide framework were evaluated in vitro against Plasmodium falciparum. They exhibited moderate to good activities.

Mots clés: C-centered radical; cyclic peroxide; hybrid molecules; malaria

Domaines: Chimie; Chimie organique

Jérémy Ruiz, Joëlle Azéma, Corinne Payrastre, Michel Baltas, Beátrice Tuccio, et al.. Antimalarial Bicyclic Peroxides Belonging to the G-Factor Family: Mechanistic Aspects of their Formation and Iron (II) Induced Reduction. Current Topics in Medicinal Chemistry, 2014, 14 (14), pp.1668-1683. ⟨10.2174/1568026614666140808154326⟩. ⟨hal-02322051⟩