Small phenolic inhibitors of PfATP6, a Plasmodium falciparum calcium ATPase, as prototype antimalarials

Malaria, an infectious disease caused by Plasmodium parasites, continues to pose a serious global health problem. PfATP6, a calcium-transporting transmembrane protein present in Plasmodium falciparum, has been identified as a promising target for new antimalarial drugs, prompting searches for specific and potent inhibitors of this enzyme. Such compounds also have the potential of becoming novel research tools for the elucidation of the enzyme's physiological functions. However, only a few PfATP6 inhibitors are known to date and most of them suffer from limitations due to their high structural complexity, with high costs that restrict their availability. A notable exception is a group of structurally simple phenolic compounds that feature hydroquinone and naphthoquinone scaffolds. In order to assess the potential of this compound class as future antimalarials, we characterized a small library of these molecules in P. falciparum blood stage viability and PfATP6 activity inhibition assays. Several compounds were able to inhibit parasite growth, amongst them di-alkylated hydroquinones, a naphthoquinone disulfide, and hexachlorophene, a disinfectant. Some of the antiplasmodial compounds were also able to inhibit the activity of the purified enzyme, even though the correlation between these two properties was not absolute. The molecular interactions of active compounds with PfATP6 were analyzed by homology modeling, ligand docking, and molecular dynamics simulations, revealing a combination of hydrogen bonding and hydrophobic interactions as the main contributors to binding. The gained information constitutes a first step toward the future design of small-molecule PfATP6 inhibitors with improved properties.