Abstract
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.
Original language | English |
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Pages (from-to) | 1962-1967 |
Number of pages | 6 |
Journal | ACS Medicinal Chemistry Letters |
Volume | 12 |
Issue number | 12 |
DOIs | |
State | Published - 9 Dec 2021 |
Keywords
- Malaria
- P. falciparum drug target
- PfPKG inhibitor
- cellular activity
- protein kinase inhibitor