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 (-0.88V<E(1/2)<-0.50V vs. SCE) was attributed to the reduction of the N-oxide function to form a radical nitroxide anion. The second reduction (-1.65V<E(1/2)<-1.14V 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 R(1)=-OCH(3), R(2)=H, and electron-withdrawing substituents on the phenyl group at R(3). The results help in the design of new molecules with more potent in vivo antimalarial activity.