Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

Jopaul Mathew; Sha Ding; Kevin A. Kunz; Emily E. Stacy; Joshua H. Butler; Reagan S. Haney; Emilio F. Merino; Grant J. Butschek; Zaira Rizopoulos; Maxim Totrov; Maria B. Cassera; Paul R. Carlier

doi:10.1021/acsmedchemlett.1c00663

Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

Jopaul Mathew
, Sha Ding
, Kevin A. Kunz
, Emily E. Stacy
, Joshua H. Butler
, Reagan S. Haney
, Emilio F. Merino
, Grant J. Butschek
, Zaira Rizopoulos
, Maxim Totrov
, Maria B. Cassera
, Paul R. Carlier

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

21 Scopus citations

Abstract

Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.

Original language	English
Pages (from-to)	365-370
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	13
Issue number	3
DOIs	https://doi.org/10.1021/acsmedchemlett.1c00663
State	Published - Mar 10 2022
Externally published	Yes

Funding

P.R.C., M.B.C., and M.T. thank the National Institutes of Health (AI128362 and AI157445) for financial support. We gratefully acknowledge E. Winzeler and D. A Kyle for providing the Dd2-KAE609 and 4G strains of P. falciparum, respectively. Part of the data presented in this manuscript are included in patent WO2021/195603 A1 (PCT/US2021/024542), filed on behalf of Virginia Polytechnic Institute and State University, Virginia Tech Intellectual Properties, Inc., and the University of Georgia Research Foundation Inc. R P.R.C., M.B.C., and M.T. thank the National Institutes of Health (AI128362 and AI157445) for financial support. We gratefully acknowledge E. Winzeler and D. A Kyle for providing the Dd2-KAE609R and 4G strains of P. falciparum, respectively. Part of the data presented in this manuscript are included in patent WO2021/195603 A1 (PCT/US2021/024542), filed on behalf of Virginia Polytechnic Institute and State University, Virginia Tech Intellectual Properties, Inc., and the University of Georgia Research Foundation Inc.

Keywords

DMPK
Drug discovery
Plasmodium
in vivo
synthesis

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10.1021/acsmedchemlett.1c00663

Cite this

Mathew, J., Ding, S., Kunz, K. A., Stacy, E. E., Butler, J. H., Haney, R. S., Merino, E. F., Butschek, G. J., Rizopoulos, Z., Totrov, M., Cassera, M. B., & Carlier, P. R. (2022). Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials. ACS Medicinal Chemistry Letters, 13(3), 365-370. https://doi.org/10.1021/acsmedchemlett.1c00663

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title = "Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials",

abstract = "Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.",

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month = mar,

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doi = "10.1021/acsmedchemlett.1c00663",

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Mathew, J, Ding, S, Kunz, KA, Stacy, EE, Butler, JH, Haney, RS, Merino, EF, Butschek, GJ, Rizopoulos, Z, Totrov, M, Cassera, MB & Carlier, PR 2022, 'Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials', ACS Medicinal Chemistry Letters, vol. 13, no. 3, pp. 365-370. https://doi.org/10.1021/acsmedchemlett.1c00663

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T1 - Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

AU - Mathew, Jopaul

AU - Ding, Sha

AU - Kunz, Kevin A.

AU - Stacy, Emily E.

AU - Butler, Joshua H.

AU - Haney, Reagan S.

AU - Merino, Emilio F.

AU - Butschek, Grant J.

AU - Rizopoulos, Zaira

AU - Totrov, Maxim

AU - Cassera, Maria B.

AU - Carlier, Paul R.

PY - 2022/3/10

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AB - Virtual ligand screening of a publicly available database of antimalarial hits using a pharmacophore derived from antimalarial MMV008138 identified TCMDC-140230, a tetrahydro-β-carboline amide, as worthy of exploration. All four stereoisomers of this structure were synthesized, but none potently inhibited growth of the malaria parasite Plasmodium falciparum. Interestingly, 7e, a minor byproduct of these syntheses, proved to be potent in vitro against P. falciparum and was orally efficacious (40 mg/kg) in an in vivo mouse model of malaria.

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KW - Drug discovery

KW - Plasmodium

KW - in vivo

KW - synthesis

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SP - 365

EP - 370

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IS - 3

ER -

Malaria Box-Inspired Discovery of N-Aminoalkyl-β-carboline-3-carboxamides, a Novel Orally Active Class of Antimalarials

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Keywords

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