Potential of caffeic acid derivatives as antimalarial leads.

Malaria remains one of the deadliest infectious disease in 2021. Indeed, this infection, mostly caused by a protozoon called Plasmodium falciparum, is responsible annually for more than 200 million cases and around 400 000 related deaths, mainly in Africa. Despite the availability of efficient drugs, we observe an increase of patients since 2015, which could find its origin in development of resistances from the parasite but also from its vectors, Anopheles mosquitoes. Consequently, it is necessary to search for new alternative treatments. Polyphenols, and more precisely small phenolic acids, could represent a good starting point for new antimalarials. Indeed, these molecules, such as caffeic acid (1), exhibit several pharmacological activities and an interesting pharmacokinetic profile. Therefore, we have developed several small derivatives of this scaffold to define the potential pharmacophore responsible for the antiplasmodial properties. We have obtained a good to low activity on Plasmodium (IC50 = 16-241 µM) with selectivity against human cells, especially for small esters (2-6, SI > 3). These structures have highlighted the need of catechol and carboxyl moieties in the anti-Plasmodium effect. Unfortunately, none of them seemed sufficiently effective to become a new antimalarial, but they could be new leads for future development.