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

Chemistry and Biochemistry

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

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
Journal	ACS Medicinal Chemistry Letters
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00540
State	Accepted/In press - 2021

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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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. (Accepted/In press). Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.1c00540

@article{7970c826d4004e78b93e37e8847f9a35,

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 = "cellular activity, Malaria, P. falciparum drug target, PfPKG inhibitor, 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.}",

note = "Funding Information: This research was supported by the Sokol Institute for Pharmaceutical Life Sciences (J.J.S. and D.P.R.), the National Institutes of Health (RO1-AI-133633-01 to J.J.S., P.B., and D.P.R.), and the Military Infectious Disease Research Program (Q0480_19_WR_CS_OC to B.S.P. and P.L.). Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

doi = "10.1021/acsmedchemlett.1c00540",

language = "English",

journal = "ACS Medicinal Chemistry Letters",

issn = "1948-5875",

publisher = "American Chemical Society",

}

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. https://doi.org/10.1021/acsmedchemlett.1c00540

TY - JOUR

T1 - Discovery of Imidazole-Based Inhibitors of Plasmodium falciparum cGMP-Dependent Protein Kinase

AU - Bheemanaboina, Rammohan R.Yadav

AU - De Souza, Mariana Laureano

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.

N1 - Funding Information: This research was supported by the Sokol Institute for Pharmaceutical Life Sciences (J.J.S. and D.P.R.), the National Institutes of Health (RO1-AI-133633-01 to J.J.S., P.B., and D.P.R.), and the Military Infectious Disease Research Program (Q0480_19_WR_CS_OC to B.S.P. and P.L.). Publisher Copyright: © 2021 American Chemical Society.

PY - 2021

Y1 - 2021

N2 - 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.

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.

KW - cellular activity

KW - Malaria

KW - P. falciparum drug target

KW - PfPKG inhibitor

KW - protein kinase inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85119973893&partnerID=8YFLogxK

U2 - 10.1021/acsmedchemlett.1c00540

DO - 10.1021/acsmedchemlett.1c00540

M3 - Article

AN - SCOPUS:85119973893

SN - 1948-5875

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

ER -

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

Abstract

Keywords

UN SDGs

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