N,N′-bridged heterocyclic bis-iminium salts as potent antimalarial agents against multi-resistant Plasmodium falciparum

The emergence of Plasmodium resistance to past and newly introduced antimalarial drugs reinforces the need for new antimalarial agents with innovative mechanisms of action. In this regard, the search for new redox-cycling compounds might offer an interesting approach to treat malaria since P. falciparum is sensitive to oxidative stress. Based on our experience in the design of powerful organic reducers, we undertook here the synthesis and evaluation of different families of N-heterocyclic iminium salts that could provide more selective redox-cycling candidates against the K1 multi-resistant Plasmodium falciparum strain (PfK1). Bis-aminopyridinium salts emerged as the most promising candidates, exhibiting nanomolar antiplasmodial activity comparable to that of methylene blue. The biological study also underlined the positive impact on the in vitro activity of electron-donating groups and bis-salt forms, likely due to simultaneous bivalent interactions with the target. Our investigations revealed differences in the mechanism of action according to the heterocycle nature, highlighting an original mechanism for bis-aminopyridinium derivatives, different from that of chloroquine.