Discovery of 6'-chloro-N-methyl-5'-(phenylsulfonamido)-[3,3'-bipyridine]-5-carboxamide (CHMFL-PI4K-127) as a novel Plasmodium falciparum PI(4)K inhibitor with potent antimalarial activity against both blood and liver stages of Plasmodium.

Starting from a bipyridine-sulfonamide scaffold, medicinal chemistry optimization leads to the discovery of a novel Plasmodium falciparum PI4K kinase (PfPI4K) inhibitor compound 15g (CHMFL-PI4K-127, IC ₅₀ : 0.9 nM), which exhibits potent activity against 3D7 Plasmodium falciparum (P. falciparum) (EC ₅₀ : 25.1 nM). CHMFL-PI4K-127 displays high selectivity against PfPI4K over human lipid and protein kinase. In addition, it exhibits EC ₅₀ values of 23-47 nM against a panel of the drug-resistant strains of P. falciparum. In vivo, the inhibitor demonstrates the favorable pharmacokinetic properties in both rats and mice. Furthermore, oral administration of CHMFL-PI4K-127 exhibits the antimalaria efficacy in both blood stage (80 mg/kg) and liver stage (1 mg/kg) of Plasmodium in infected rodent model. The results suggest that CHMFL-PI4K-127 might be a new potential drug candidate for malaria.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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