Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum ATP4 (PfATP4)

Malaria, caused by parasites of the Plasmodium species and transmitted through the bites of infected female Anopheles mosquitoes, is still a fatal and dangerous disease in mainly tropical and subtropical regions. The widespread resistance of P. falciparum to antimalarial drugs forces the search for new molecules with activity against this parasite. While a large number of compounds can inhibit P. falciparum growth in vitro, unfortunately, only a limited number of targets have been identified so far. One of the most promising approaches has been the identification of effective inhibitors of P-type cation-transporter ATPase 4 (PfATP4) in P. falciparum. PfATP4 is a Na+ efflux pump that maintains a low cytosolic Na+ in the parasite. Thus, upon treatment with PfATP4 inhibitors, the parasites rapidly accumulate Na+, which triggers processes leading to parasite death. PfATP4 is present in the parasite plasma membrane but is absent in mammals; its exclusivity thus makes it a good antimalarial drug target. The current review presents PfATP4 function in the context of the pharmacological influence of its inhibitors. In addition, compounds with inhibitory activities belonging to spiroindolones, dihydroisoquinolones, aminopyrazoles, pyrazoleamides, and 4-cyano-3-methylisoquinolines, are also reviewed. Particular emphasis is placed on the results of preclinical and clinical studies in which their effectiveness was tested. PfATP4-associated antimalarials rapidly cleared parasites in mouse models and preliminary human trials. These findings highlight a fundamental biochemical mechanism sensitive to pharmacological intervention that can form a medicinal chemistry approach for antimalarial drug design to create new molecules with potent PfATP4 inhibitory activity.