Pro-oxidant properties of indolone-N-oxides in relation to their antimalarial properties
Nguyen Thi Hoang Yen1, Hany Ibrahim, Karine Reybier
1Université de Toulouse, UPS, UMR 152 PHARMA-DEV, 118 route de Narbonne, F-31062 Toulouse cedex 9, France.
Abstract:
Indolone-N-oxides (INODs) are bioreducible and possess remarkable anti-malarial activities in the low nanomolar range in vitro against different Plasmodium falciparum (P. falciparum) strains and in vivo. INODs have an original mechanism of action: they damage the host cell membrane without affecting non-parasitized erythrocytes. These molecules produce a redox signal which activates SYK tyrosine kinases and induces a hyperphosphorylation of AE1 (band 3, erythrocyte membrane protein). The present work aimed to understand the early stages of the biochemical interactions of these compounds with some erythrocyte components from which the redox signal could originate. The interactions were studied in a biomimetic model and compared with those of chloroquine and artemisinin. The results showed that INODs i) do not enter the coordination sphere of the metal in the heme iron complex as does chloroquine; ii) do not generate iron-dependent radicals as does artemisinin; iii) generate stable free radical adducts after reduction at one electron; iv) cannot trap free radicals after reduction. These results confirm that the bioactivity of INODs does not lie in their spin-trapping properties but rather in their pro-oxidant character. This property may be the initiator of the redox signal which activates SYK tyrosine kinases.
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