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

Rammohan R.Yadav Bheemanaboina, Mariana Laureano De Souza, Mariana Lozano Gonzalez, Shams Ul Mahmood, Tyler Eck, Tamara Kreiss, Samantha O. Aylor, Alison Roth, Patricia Lee, Brandon S. Pybus, Dennis J. Colussi, Wayne E. Childers, John Gordon, John J. Siekierka, Purnima Bhanot, David P. Rotella

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish
JournalACS Medicinal Chemistry Letters
DOIs
StateAccepted/In press - 2021

Keywords

  • cellular activity
  • Malaria
  • P. falciparum drug target
  • PfPKG inhibitor
  • protein kinase inhibitor

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