Plasmodium falciparum kinases have been widely studied due to their potential as targets for the discovery of alternatives to artemisinin-combined therapies. Their role in parasite blood-stage replication and their homology with human kinases has led to the exploitation of already tested antitumoral kinase inhibitors as antiplasmodial drugs. Plasmodium falciparum choline kinase (PfCK), a cytosolic enzyme involved in phospholipid synthesis, is a promising target for parasite resistant strains. PfCK uses the host choline and catalyzes its transformation in phosphocholine, a key step for the formation of the lipid membranes required by the new parasite progeny inside the erythrocyte. Previously, we described the synthesis of two libraries (PL and FP) of human choline kinase (hCK) inhibitors, which we generated following a green by design approach. Some of these compounds were found to exhibit antitumoral properties. Here, we evaluated the same compounds as potential inhibitors of PfCK and antimalarial agents. Interestingly, while the compounds of the FP library, which feature a disulphide linker, show PfCK inhibition in the nM range independently of the cationic head (FP3 being the most active compound, PfCK IC50 = 0.16 μM), they show no effect on infected erythrocytes. On the other hand, the compounds of the PL library, which feature a dithioethane linker, show in vitro activity against the parasite but no inhibitory activity against the isolated enzyme (PL40 exhibits the highest antimalarial activity, with IC50 = 10 nM). This lack of correlation could be due to either cellular disulphide degradation in vitro or to the existence of alternative targets for the dithioethane library. Considering the previously reported anticancer potential of the PL family and the antiparasitic activity reported herein, these compounds may be considered as good starting points for the development of multifunctional drugs.
Biological evaluation as antimalarial of two families of biscationic compounds featuring two different sulphur linkers
Luque Navarro, Pilar M.;Lanari, Daniela;
2025
Abstract
Plasmodium falciparum kinases have been widely studied due to their potential as targets for the discovery of alternatives to artemisinin-combined therapies. Their role in parasite blood-stage replication and their homology with human kinases has led to the exploitation of already tested antitumoral kinase inhibitors as antiplasmodial drugs. Plasmodium falciparum choline kinase (PfCK), a cytosolic enzyme involved in phospholipid synthesis, is a promising target for parasite resistant strains. PfCK uses the host choline and catalyzes its transformation in phosphocholine, a key step for the formation of the lipid membranes required by the new parasite progeny inside the erythrocyte. Previously, we described the synthesis of two libraries (PL and FP) of human choline kinase (hCK) inhibitors, which we generated following a green by design approach. Some of these compounds were found to exhibit antitumoral properties. Here, we evaluated the same compounds as potential inhibitors of PfCK and antimalarial agents. Interestingly, while the compounds of the FP library, which feature a disulphide linker, show PfCK inhibition in the nM range independently of the cationic head (FP3 being the most active compound, PfCK IC50 = 0.16 μM), they show no effect on infected erythrocytes. On the other hand, the compounds of the PL library, which feature a dithioethane linker, show in vitro activity against the parasite but no inhibitory activity against the isolated enzyme (PL40 exhibits the highest antimalarial activity, with IC50 = 10 nM). This lack of correlation could be due to either cellular disulphide degradation in vitro or to the existence of alternative targets for the dithioethane library. Considering the previously reported anticancer potential of the PL family and the antiparasitic activity reported herein, these compounds may be considered as good starting points for the development of multifunctional drugs.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
