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Bistacrines as potential antitrypanosomal agents.

Ines Schmidt1, Sarah Göllner2, Antje Fuß3

  • 1Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany.

Bioorganic & Medicinal Chemistry
|July 13, 2017
PubMed
Summary

New tacrine derivatives show promise in treating Human African Trypanosomiasis (HAT). These compounds effectively inhibit parasite growth, offering potential new therapies for this fatal disease.

Keywords:
Antitrypanosomal drugsBistacrineRhodesainTrypanothione reductase

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Area of Science:

  • Medicinal Chemistry
  • Parasitology
  • Drug Discovery

Background:

  • Human African Trypanosomiasis (HAT) is a fatal parasitic disease with limited treatment options.
  • Existing therapies for HAT are inadequate, necessitating the development of novel therapeutic agents.
  • Dimeric tacrine derivatives have demonstrated preliminary efficacy against parasite growth.

Purpose of the Study:

  • To synthesize and evaluate a library of monomeric and dimeric tacrine-type compounds for antiprotozoal activity.
  • To identify potential drug targets for HAT therapy among the synthesized compounds.
  • To explore the mechanism of action of effective tacrine derivatives against Trypanosoma parasites.

Main Methods:

  • Synthesis of a focused library of monomeric and dimeric tacrine derivatives.
  • In vitro evaluation of antiprotozoal activity using IC50 values.
  • Investigating the inhibition of key parasite enzymes, including rhodesain and trypanothione reductase.

Main Results:

  • Several tacrine derivatives exhibited potent inhibition of parasite growth in the nanomolar range.
  • Rhodesain, a cysteine protease essential for parasite survival, was identified as a likely target.
  • Bistacrines demonstrated inhibition of trypanothione reductase, a crucial enzyme in the parasite's oxidative stress defense.

Conclusions:

  • Monomeric and dimeric tacrine derivatives represent a promising class of compounds for HAT drug development.
  • Targeting rhodesain and trypanothione reductase are viable strategies for combating HAT.
  • Further investigation into these compounds could lead to effective treatments for Human African Trypanosomiasis.