Potential of Caffeic Acid Derivatives as Antimalarial Leads

Background: Malaria was one of the deadliest infectious diseases in 2021. Indeed, this infection, mostly caused by a protozoan called Plasmodium falciparum, is responsible for more than 200 million cases and around 400 000 related deaths annually, mainly in Africa. Despite the availability of effective drugs, the number of patients has increased since 2015, which could be due to parasite resistance as well as resistance in the pathogen's vectors, Anopheles mosquitoes. Consequently, it is necessary to search for new alternative treatments. Methods: Polyphenols, more precisely small phenolic acids, could represent a good starting point for new antimalarials. Indeed, these molecules, including caffeic acid (1), possess 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. Results: A good to low activity on Plasmodium falciparum (IC50 = 16-241 μM) was observed, especially for the small ester derivatives (2-6). These molecules were good antiplasmodials compared to their mother compound (IC50 = 80 μM) and showed selectivity against human cells. These structures have also highlighted the need for catechol and carboxyl moieties in the anti-Plasmodium effect. Conclusion: None of the synthetic caffeate derivatives reported here seemed sufficiently effective to become a potential antimalarial (IC50 < 1 μM). However, the significant increase of their efficacy on the malarial agent and the selectivity to human cells highlighted their potential as new leads for future developments.