2. Academic Validation
  3. Bistacrines as potential antitrypanosomal agents

Bistacrines as potential antitrypanosomal agents

  • Bioorg Med Chem. 2017 Aug 15;25(16):4526-4531. doi: 10.1016/j.bmc.2017.06.051.
Ines Schmidt 1,  Sarah Göllner 2,  Antje Fuß 3,  August Stich 3,  Anna Kucharski 1,  Tanja Schirmeister 4,  Elena Katzowitsch 5,  Heike Bruhn 5,  Alexandra Miliu 2,  R Luise Krauth-Siegel 2,  Ulrike Holzgrabe 6
Affiliations

Affiliations

  • 1 Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany.
  • 2 Biochemistry Center (BZH), Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
  • 3 Medical Mission Institute, Hermann-Schell-Strasse 7, 97074 Würzburg, Germany.
  • 4 Institute for Pharmacy and Biochemistry, Johannes-Gutenberg-University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany.
  • 5 Institute for Molecular Infection Biology, Julius-Maximilians-University of Würzburg, Josef-Schneider-Strasse 2, 97080 Würzburg, Germany.
  • 6 Institute for Pharmacy and Food Chemistry, Julius-Maximilians-University of Würzburg, Am Hubland, 97074 Würzburg, Germany. Electronic address: ulrike.holzgrabe@uni-wuerzburg.de.
PMID: 28698054 DOI: 10.1016/j.bmc.2017.06.051
Abstract

Human African Trypanosomiasis (HAT) is caused by two subspecies of the genus Trypanosoma, namely Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. The disease is fatal if left untreated and therapy is limited due to only five non-adequate drugs currently available. In preliminary studies, dimeric tacrine derivatives were found to inhibit Parasite growth with IC50-values in the nanomolar concentration range. This prompted the synthesis of a small, but smart library of monomeric and dimeric tacrine-type compounds and their evaluation of antiprotozoal activity. Rhodesain, a lysosomal cathepsin-L like cysteine protease of T. brucei rhodesiense is essential for Parasite survival and likely target of the tacrine derivatives. In addition, the inhibition of trypanothione reductase by bistacrines was found. This flavoprotein oxidoreductase is the main defense against oxidative stress in the thiol redox system unique for protozoa.

Keywords

Antitrypanosomal drugs; Bistacrine; Rhodesain; Trypanothione reductase.

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