Dataset Information

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

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.

SUBMITTER: Bheemanaboina RRY

PROVIDER: S-EPMC8667308 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Discovery of Imidazole-Based Inhibitors of <i>Plasmodium falciparum</i> cGMP-Dependent Protein Kinase.

Bheemanaboina Rammohan R Yadav RRY de Souza Mariana Laureano ML Gonzalez Mariana Lozano ML Mahmood Shams Ul SU Eck Tyler T Kreiss Tamara T Aylor Samantha O SO Roth Alison A Lee Patricia P Pybus Brandon S BS Colussi Dennis J DJ Childers Wayne E WE Gordon John J Siekierka John J JJ Bhanot Purnima P Rotella David P DP

ACS medicinal chemistry letters 20211115 12

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 <i>Plasmodium falciparum</i> 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 ...[more]

PMID: 34917261

Dataset Information

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

Publications

Discovery of Imidazole-Based Inhibitors of <i>Plasmodium falciparum</i> cGMP-Dependent Protein Kinase.

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