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 journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)784-794
Number of pages11
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Volume27
Issue number6
DOIs
StatePublished - Dec 2012
Externally publishedYes

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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