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Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2021 Nov 15; Vol. 12 (12), pp. 1962-1967. Date of Electronic Publication: 2021 Nov 15 (Print Publication: 2021). - Publication Year :
- 2021
-
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.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2021 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 12
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 34917261
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.1c00540