Development of Novel Enantiopure Aminopyridine Alcohols as Promising Antimalarial Agents

Malaria remains a major global public health challenge, particularly in sub-Saharan Africa. According to the World Health Organization, malaria cases increased by 3% compared with 2023, reaching 282 million cases with approximately 610,000 deaths in 2024. The disease is caused by Plasmodium parasites, transmitted through the bites of female Anopheles mosquitoes. Among the five Plasmodium species infecting humans, P. falciparum is the most prevalent species in Africa and the most lethal. The emergence and spread of resistance to artemisinin-based combination therapies (ACTs), the first-line treatments recommended by the WHO, represent a major threat to malaria control.

Resistance to ACTs has been associated with mutations in the pfk13 gene, which are linked to artemisinin resistance, as well as alterations in Pf multidrug resistance 1 (PfMDR1), a transporter involved in the influx of nutrients and molecules, including arylaminoalcohols from the parasite cytosol into the digestive vacuole. These genetic and molecular adaptations compromise the efficacy of ACTs, highlighting the critical need for the development of new antimalarial agents.

Herein, we report the design and synthesis of 30 novel enantiopure aminopyridine alcohols based on both the enpiroline scaffold and a first hit identified by our team. A short and optimized synthetic route was developed, and the resulting compounds were evaluated for their physicochemical properties and in vitro antiplasmodial activity. Most compounds exhibited strong antiplasmodial activity against both the 3D7 and W2 P. falciparum strains, with IC₅₀ values below 50 nM. Cytotoxicity assays against a mammalian cell line revealed excellent selectivity indices, mostly exceeding 150. Structure-activity relationship studies identified key substituents that enhanced antimalarial activity and selectivity, highlighting a promising compound. Further studies will focus on characterizing its pharmacokinetic properties and evaluation of its in vivo efficacy to confirm whether this promising compound can be validated as a new antimalarial hit.