The
discovery of new targets for the treatment of malaria, in particular
those aimed at the pre-erythrocytic stage in the life cycle, advanced
with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase
(PfPKG) could clear infection in a murine model. This enthusiasm was
tempered by unsatisfactory safety and/or pharmacokinetic issues found
with these chemotypes. To address the urgent need for new scaffolds,
this paper presents initial structure–activity relationships
in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization, and cell-based antiparasitic
activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity, and cell-based antiparasitic activity
against multiple Plasmodium species
that appears to be correlated with the in vitro potency.
The discovery of new targets for treatment of malaria advanced with the demonstration that orally administered inhibitors of Plasmodium falciparum cGMP-dependent protein kinase (PfPKG) could clear infection in a murine model. This enthusi-asm was tempered by unsatisfactory safety and/or pharmacokinetic issues found with these chemotypes. To address the urgent need for new scaffolds, we recently reported the discovery and optimization of novel, potent isoxazole-based PfPKG inhibitors that lacked any obvious safety warnings. This manuscript presents representative in vitro ADME, hERG charac-terization and cell-based antiparasitic activity of these PfPKG inhibitors. We also report the discovery and structure-activity relationships of a new series with good potency, low hERG activity and cell-based anti-parasitic activity comparable to a literature standard.
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