ABSTRACT
The discovery of new targets for treatment of malaria and 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 manuscript presents initial structure-activity relationships in an imidazole scaffold at four positions, representative in vitro ADME, hERG characterization and cell-based anti-parasitic activity. This series of PfPKG inhibitors has good in vitro PfPKG potency, low hERG activity and cell-based anti-parasitic activity against multiple Plasmodium species that appears to correlate with in vitro potency.
Competing Interest Statement
The authors have declared no competing interest.
ABBREVIATIONS
- PfPKG
- Plasmodium falciparum
- cGMP
- dependent protein kinase
- PbLuc
- Plasmodium berghei luciferase
- SAR
- structure-activity relationship
- ATP
- adenosine triphosphate
- ADME
- absorption, distribution, metabolism, elimination
- CYP3A4
- cytochrome P450 3A4
- hERG
- human ether-a-go-go related gene.