2. Academic Validation
  3. Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase

Inhibitory effect of phenothiazine- and phenoxazine-derived chloroacetamides on Leishmania major growth and Trypanosoma brucei trypanothione reductase

  • Eur J Med Chem. 2016 Jan 27:108:436-443. doi: 10.1016/j.ejmech.2015.11.023.
Ana Marcu 1,  Uta Schurigt 2,  Klaus Müller 3,  Heidrun Moll 1,  R Luise Krauth-Siegel 4,  Helge Prinz 5
Affiliations

Affiliations

  • 1 Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany.
  • 2 Institute for Molecular Infection Biology, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany. Electronic address: uta.schurigt@uni-wuerzburg.de.
  • 3 Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany.
  • 4 Biochemistry Center of Heidelberg University (BZH), Im Neuenheimer Feld 504, D-69120 Heidelberg, Germany.
  • 5 Institute of Pharmaceutical and Medicinal Chemistry, University of Muenster, Corrensstraße 48, D-48149 Muenster, Germany. Electronic address: prinzh@uni-muenster.de.
PMID: 26708110 DOI: 10.1016/j.ejmech.2015.11.023
Abstract

A number of phenothiazine-, phenoxazine- and related tricyclics-derived chloroacetamides were synthesized and evaluated in vitro for antiprotozoal activities against Leishmania major (L. major) promastigotes. Several analogs were remarkably potent inhibitors, with antileishmanial activities being comparable or superior to those of the reference antiprotozoal drugs. Furthermore, we explored the structure-activity relationships of N-10 haloacetamides that influence the potency of such analogs toward inhibition of L. major promastigote growth in vitro. With respect to the mechanism of action, selected compounds were evaluated for time-dependent inactivation of Trypanosoma brucei trypanothione reductase. Our results are indicative of a covalent interaction which could account for potent antiprotozoal activities.

Keywords

Antileishmanial activity; Chloroacetamides; Phenothiazines; Phenoxazines; Trypanothione reductase.

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