1. Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase
- Author
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Tyler Eck, John Gordon, Wayne E. Childers, Brandon S. Pybus, Dennis J. Colussi, Tamara Kreiss, Alison Roth, Rammohan R. Yadav Bheemanaboina, David P. Rotella, Shams Ul Mahmood, Patricia J. Lee, Purnima Bhanot, Samantha O. Aylor, Mariana Laureano de Souza, Mariana Lozano Gonzalez, and John J. Siekierka
- Subjects
Cellular activity ,biology ,medicine.drug_class ,Organic Chemistry ,Plasmodium falciparum ,Protein kinase inhibitor ,Pharmacology ,medicine.disease ,biology.organism_classification ,Biochemistry ,chemistry.chemical_compound ,chemistry ,parasitic diseases ,Drug Discovery ,medicine ,Imidazole ,cGMP-dependent protein kinase ,Malaria - Abstract
[Image: see text] 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.
- Published
- 2021