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

doi:10.1021/acsmedchemlett.1c00540

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

New Jersey Medical School (NJMS), Microbiology

Research output: Contribution to journal › Article › peer-review

3 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 language	English (US)
Pages (from-to)	1962-1967
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	12
Issue number	12
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00540
State	Published - Dec 9 2021

All Science Journal Classification (ASJC) codes

Biochemistry
Drug Discovery
Organic Chemistry

Keywords

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

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10.1021/acsmedchemlett.1c00540

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Bheemanaboina, R. R. Y., De Souza, M. L., Gonzalez, M. L., Mahmood, S. U., Eck, T., Kreiss, T., Aylor, S. O., Roth, A., Lee, P., Pybus, B. S., Colussi, D. J., Childers, W. E., Gordon, J., Siekierka, J. J., Bhanot, P., & Rotella, D. P. (2021). Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase. ACS Medicinal Chemistry Letters, 12(12), 1962-1967. https://doi.org/10.1021/acsmedchemlett.1c00540

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title = "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.",

keywords = "Malaria, P. falciparum drug target, PfPKG inhibitor, cellular activity, protein kinase inhibitor",

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

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doi = "10.1021/acsmedchemlett.1c00540",

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Bheemanaboina, RRY, De Souza, ML, Gonzalez, ML, Mahmood, SU, Eck, T, Kreiss, T, Aylor, SO, Roth, A, Lee, P, Pybus, BS, Colussi, DJ, Childers, WE, Gordon, J, Siekierka, JJ, Bhanot, P & Rotella, DP 2021, 'Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase', ACS Medicinal Chemistry Letters, vol. 12, no. 12, pp. 1962-1967. https://doi.org/10.1021/acsmedchemlett.1c00540

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AU - Gonzalez, Mariana Lozano

AU - Mahmood, Shams Ul

AU - Eck, Tyler

AU - Kreiss, Tamara

AU - Aylor, Samantha O.

AU - Roth, Alison

AU - Lee, Patricia

AU - Pybus, Brandon S.

AU - Colussi, Dennis J.

AU - Childers, Wayne E.

AU - Gordon, John

AU - Siekierka, John J.

AU - Bhanot, Purnima

AU - Rotella, David P.

PY - 2021/12/9

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AB - 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.

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KW - cellular activity

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ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Keywords

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