2. Academic Validation
  3. Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates

Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates

  • Bioorg Med Chem. 2017 Jan 1;25(1):84-90. doi: 10.1016/j.bmc.2016.10.013.
Elodie Jagu 1,  Sébastien Pomel 2,  Alba Diez-Martinez 1,  Florence Ramiandrasoa 1,  R Luise Krauth-Siegel 3,  Stéphanie Pethe 1,  Casimir Blonski 1,  Raphaël Labruère 4,  Philippe M Loiseau 5
Affiliations

Affiliations

  • 1 Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), CNRS, Univ Paris Sud, Université Paris-Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France.
  • 2 Chimiothérapie antiparasitaire, UMR 8076 BioCis, CNRS, Univ Paris Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France.
  • 3 Center of Biochemistry of Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
  • 4 Institut de Chimie Moléculaire et des Matériaux d'Orsay (ICMMO), CNRS, Univ Paris Sud, Université Paris-Saclay, 15 rue Georges Clemenceau, 91405 Orsay Cedex, France. Electronic address: raphael.labruere@u-psud.fr.
  • 5 Chimiothérapie antiparasitaire, UMR 8076 BioCis, CNRS, Univ Paris Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France. Electronic address: philippe.loiseau@u-psud.fr.
PMID: 27793448 DOI: 10.1016/j.bmc.2016.10.013
Abstract

Thirteen new polyamine derivatives coupled to hydroxybenzotriazole have been synthesized and evaluated for their in vitro antikinetoplastid activity. Trypanosoma Trypanothione reductase (TryR) was envisioned as a potential target. Among all tested molecules, only one compound, a N3-spermidine-benzotriazole derivative, displayed relevant inhibitory activity on this Enzyme but was not active on parasites. The corresponding Boc-protected spermidine-benzotriazole was however trypanocidal against Trypanosoma brucei gambiense with an IC50 value of 1μM and was completely devoid of cytotoxicity. On the intramacrophage amastigotes of Leishmania donovani, a N2-spermidine conjugate of this series, exhibited an interesting IC50 value of 3μM associated with both low cytotoxicity against axenic Leishmania donovani. These new compounds are promising leads for the development of antikinetoplastid agents and their targets have to be deciphered.

Keywords

Antikinetoplastids; Benzotriazole; Leishmania donovani; Polyamines; Trypanosoma brucei; Trypanothione reductase.

Figures