Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase

Authors

• Rammohan R. Yadav Bheemanaboina, Montclair State UniversityFollow
• Mariana Laureano de Souza, Rutgers New Jersey Medical School
• Mariana Lozano Gonzalez, Montclair State UniversityFollow
• Shams ul Mahmood, Montclair State UniversityFollow
• Tyler Eck, Montclair State UniversityFollow
• Tamara Kreiss, Montclair State UniversityFollow
• Samantha O. Aylor, Walter Reed Army Institute of Research
• Alison Roth, Walter Reed Army Institute of Research
• Patricia Lee, Walter Reed Army Institute of Research
• Brandon S. Pybus, Walter Reed Army Institute of Research
• Dennis J. Colussi, Temple University
• Wayne E. Childers, Temple University
• John Gordon, Temple University
• John J. Siekierka, Montclair State UniversityFollow
• Purnima Bhanot, Rutgers New Jersey Medical School
• David P. Rotella, Montclair State UniversityFollow

Document Type

Preprint

Publication Date

11-15-2021

Journal / Book Title

ACS Medicinal Chemistry Letters

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.

DOI

10.1021/acsmedchemlett.1c00540

Montclair State University Digital Commons Citation

Yadav Bheemanaboina, Rammohan R.; de Souza, Mariana Laureano; Gonzalez, Mariana Lozano; Mahmood, Shams ul; Eck, Tyler; Kreiss, Tamara; Aylor, Samantha O.; Roth, Alison; Lee, Patricia; Pybus, Brandon S.; Colussi, Dennis J.; Childers, Wayne E.; Gordon, John; Siekierka, John J.; Bhanot, Purnima; and Rotella, David P., "Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase" (2021). Department of Chemistry and Biochemistry Faculty Scholarship and Creative Works. 656.
https://digitalcommons.montclair.edu/chem-biochem-facpubs/656

Published Citation

Bheemanaboina, Rammohan R. Yadav, et al. “Discovery of Imidazole-Based Inhibitors of Plasmodium Falciparum cGMP-Dependent Protein Kinase.” ACS Medicinal Chemistry Letters, vol. 12, no. 12, Dec. 2021, pp. 1962–67. https://doi.org/10.1021/acsmedchemlett.1c00540.