Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 25, Issue 1, Pages 84-90Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2016.10.013
Keywords
Antikinetoplastids; Trypanosoma brucei; Leishmania donovani; Polyamines; Benzotriazole; Trypanothione reductase
Funding
- Initiative d'Excellence Paris-Saclay (IDEX)
- Laboratoire d'Excellence en Recherche sur le Medicament et l'Innovation Therapeutique (LabEx LERMIT)
- COST Action [CM1307]
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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 N-3-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 1 mu M and was completely devoid of cytotoxicity. On the intramacrophage amastigotes of Leishmania donovani, a N-2-spermidine conjugate of this series, exhibited an interesting IC50 value of 3 mu M 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. (C) 2016 Elsevier Ltd. All rights reserved.
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