Electrochemical behavior of indolone-N-oxides: Relationship to structure and antiplasmodial activity

Indolone-N-oxides exert high parasiticidal activity at the nanomolar level in vitro against Plasmodium falciparum, the parasite responsible for malaria. The bioreductive character of these molecules was investigated using cyclic voltammetry and EPR spectroelectrochemistry to examine the relationship between electrochemical behavior and antimalarial activity and to understand their mechanisms of action. For all the compounds (37 compounds) studied, the voltammograms recorded in acetonitrile showed a well-defined and reversible redox couple followed by a second complicated electron transfer. The first reduction (− 0.88 V < E1/2 < − 0.50 V vs. SCE) was attributed to the reduction of the N-oxide function to form a radical nitroxide anion. The second reduction (− 1.65 V < E1/2 < − 1.14 V vs. SCE) was assigned to the reduction of the ketone function. By coupling electrochemistry with EPR spectroscopy, the EPR spectra confirmed the formation of the nitroxide anion radical. Moreover, the experiments demonstrated that a slow protonation occurs at the carbon of the nitrone function and not at the NO function. A relationship between electrochemical behavior and indolone-N-oxide structure can be established for compounds with R1 = ―OCH3, R2 = H, and electron-withdrawing substituents on the phenyl group at R3. The results help in the design of new molecules with more potent in vivo antimalarial activity.

► The reduction of indolone-N-oxides was analyzed through cyclic voltammetry and EPR.
► The N-oxide functional group is reduced at Pt electrode via transfer of 1 electron to form a nitroxide anion.
► Relationship between antimalarial activity and redox potential was examined.
► For compounds having electron withdrawing substituents, the most active compounds are the most readily reduced.