title: Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates.
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 IC50value 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 IC50value 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.
authors: 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.
authors: Elodie
authors: E
authors: Jagu
authors: Chimiothérapie antiparasitaire, UMR 8076 BioCis, CNRS, Univ Paris Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France.
authors: Sébastien
authors: S
authors: Pomel
authors: 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.
authors: Alba
authors: A
authors: Diez-Martinez
authors: 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.
authors: Florence
authors: F
authors: Ramiandrasoa
authors: Center of Biochemistry of Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.
authors: R Luise
authors: RL
authors: Krauth-Siegel
authors: 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.
authors: Stéphanie
authors: S
authors: Pethe
authors: 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.
authors: Casimir
authors: C
authors: Blonski
authors: 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.
authors: Raphaël
authors: R
authors: Labruère
authors: 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.
authors: Philippe M
authors: PM
authors: Loiseau
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology; D007898:Leishmaniasis, Visceral / Q000188:drug therapy; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000981:Antiprotozoal Agents; D014230:Triazoles; D014344:Trypanocidal Agents; C012771:benzotriazole; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D013095:Spermidine
keywords: Antikinetoplastids; Benzotriazole; Leishmania donovani; Polyamines; Trypanosoma brucei; Trypanothione reductase