Malaria remains a major global public health challenge, particularly in sub-Saharan Africa. According to the World Health Organization, an estimated 263 million cases of malaria and approximately 597,000 deaths were reported in 2023. The disease is caused by Plasmodium parasites, transmitted through the bites of female Anopheles mosquitoes. Among the five species infecting humans, P. falciparum remains both the most prevalent in Africa and the most lethal. Over the past century, P. falciparum has progressively developed resistance to artemisinin-based combination therapies (ACT), the current front-line treatment recommended by the WHO.

This resistance correlates with mutations in the pfk13 gene, associated with artemisinin resistance, as well as alterations in Pf multidrug resistance 1 (PfMDR1), a transporter which regulates the influx of nutrients and molecules, including arylaminoalcohols, into the parasite’s digestive vacuole. These changes weaken the efficacy of ACT, ultimately reducing the overall effectiveness of the treatment and highlighting the urgent need to discover new effective antimalarial agents.

Herein, we report the design and synthesis of enantiopure aminopyridine derivatives built on the enpiroline scaffold as promising antimalarial compounds. Their optimized synthesis route and key physicochemical properties will be outlined, followed by an evaluation of their in vitro biological activity. Most of the compounds display potent in vitro inhibition close to the nanomolar range against both 3D7 and W2 P. falciparum strains. Cytotoxicity assays showed excellent selectivity indices, mostly above 500. A structure-activity relationship analysis will also be presented, offering valuable insights for further optimization.