Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase

Michael H. Duyzend; Christopher T. Clark; Shayna L. Simmons; Wade B. Johnson; Anna M. Larson; Aaron M. Leconte; Andrew W. Wills; Matthew Ginder-Vogel; April K. Wilhelm; Josephine A. Czechowicz; David G. Alberg

doi:10.3109/14756366.2011.604319

Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase

Michael H. Duyzend, Christopher T. Clark, Shayna L. Simmons, Wade B. Johnson, Anna M. Larson, Aaron M. Leconte, Andrew W. Wills, Matthew Ginder-Vogel, April K. Wilhelm, Josephine A. Czechowicz, David G. Alberg

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

12 Scopus citations

Abstract

Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a K_i=2 μM.

Original language	English (US)
Pages (from-to)	784-794
Number of pages	11
Journal	Journal of Enzyme Inhibition and Medicinal Chemistry
Volume	27
Issue number	6
DOIs	https://doi.org/10.3109/14756366.2011.604319
State	Published - Dec 2012
Externally published	Yes

Bibliographical note

Funding Information:
We thank the US National Institutes of Health (Grant 1 R15 AI053113-01) and the Howard Hughes Medical Institute for their generous financial support, and acknowledgment is made to the donors of The Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research. We also thank the 3M Foundation for helping to fund the purchase of a 400 MHz NMR spectrometer.

Keywords

Inhibitors
Trypanosoma cruzi
Trypanosome
Trypanothione reductase

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10.3109/14756366.2011.604319

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Duyzend, M. H., Clark, C. T., Simmons, S. L., Johnson, W. B., Larson, A. M., Leconte, A. M., Wills, A. W., Ginder-Vogel, M., Wilhelm, A. K., Czechowicz, J. A., & Alberg, D. G. (2012). Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase. Journal of Enzyme Inhibition and Medicinal Chemistry, 27(6), 784-794. https://doi.org/10.3109/14756366.2011.604319

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abstract = "Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a Ki=2 μM.",

keywords = "Inhibitors, Trypanosoma cruzi, Trypanosome, Trypanothione reductase",

author = "Duyzend, {Michael H.} and Clark, {Christopher T.} and Simmons, {Shayna L.} and Johnson, {Wade B.} and Larson, {Anna M.} and Leconte, {Aaron M.} and Wills, {Andrew W.} and Matthew Ginder-Vogel and Wilhelm, {April K.} and Czechowicz, {Josephine A.} and Alberg, {David G.}",

note = "Funding Information: We thank the US National Institutes of Health (Grant 1 R15 AI053113-01) and the Howard Hughes Medical Institute for their generous financial support, and acknowledgment is made to the donors of The Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research. We also thank the 3M Foundation for helping to fund the purchase of a 400 MHz NMR spectrometer.",

year = "2012",

month = dec,

doi = "10.3109/14756366.2011.604319",

language = "English (US)",

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pages = "784--794",

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AU - Duyzend, Michael H.

AU - Clark, Christopher T.

AU - Simmons, Shayna L.

AU - Johnson, Wade B.

AU - Larson, Anna M.

AU - Leconte, Aaron M.

AU - Wills, Andrew W.

AU - Ginder-Vogel, Matthew

AU - Wilhelm, April K.

AU - Czechowicz, Josephine A.

AU - Alberg, David G.

N1 - Funding Information: We thank the US National Institutes of Health (Grant 1 R15 AI053113-01) and the Howard Hughes Medical Institute for their generous financial support, and acknowledgment is made to the donors of The Petroleum Research Fund, administered by the American Chemical Society, for partial support of this research. We also thank the 3M Foundation for helping to fund the purchase of a 400 MHz NMR spectrometer.

PY - 2012/12

Y1 - 2012/12

N2 - Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a Ki=2 μM.

AB - Trypanothione reductase (TR) is found in the trypanosomatid parasites, where it catalyses the NADPH-dependent reduction of the glutathione analogue, trypanothione, and is a key player in the parasite's defenses against oxidative stress. TR is a promising target for the development of antitrypanosomal drugs; here, we report our synthesis and evaluation of compounds 3-5 as low micromolar Trypanosoma cruzi TR inhibitors. Although 4 and 5 were designed as potential irreversible inhibitors, these compounds, as well as 3, displayed reversible competitive inhibition. Compound 3 proved to be the most potent inhibitor, with a Ki=2 μM.

KW - Inhibitors

KW - Trypanosoma cruzi

KW - Trypanosome

KW - Trypanothione reductase

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Synthesis and evaluation of substrate analogue inhibitors of trypanothione reductase

Abstract

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