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Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates.
Bioorg Med Chem. 2017 01 01; 25(1):84-90.BM

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.

Authors+Show Affiliations

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.Chimiothérapie antiparasitaire, UMR 8076 BioCis, CNRS, Univ Paris Sud, Université Paris-Saclay, 5 rue Jean-Baptiste Clément, 92290 Châtenay-Malabry, France.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.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.Center of Biochemistry of Heidelberg University, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.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.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.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27793448

Citation

Jagu, Elodie, et al. "Synthesis and in Vitro Antikinetoplastid Activity of Polyamine-hydroxybenzotriazole Conjugates." Bioorganic & Medicinal Chemistry, vol. 25, no. 1, 2017, pp. 84-90.
Jagu E, Pomel S, Diez-Martinez A, et al. Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates. Bioorg Med Chem. 2017;25(1):84-90.
Jagu, E., Pomel, S., Diez-Martinez, A., Ramiandrasoa, F., Krauth-Siegel, R. L., Pethe, S., Blonski, C., Labruère, R., & Loiseau, P. M. (2017). Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates. Bioorganic & Medicinal Chemistry, 25(1), 84-90. https://doi.org/10.1016/j.bmc.2016.10.013
Jagu E, et al. Synthesis and in Vitro Antikinetoplastid Activity of Polyamine-hydroxybenzotriazole Conjugates. Bioorg Med Chem. 2017 01 1;25(1):84-90. PubMed PMID: 27793448.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synthesis and in vitro antikinetoplastid activity of polyamine-hydroxybenzotriazole conjugates. AU - Jagu,Elodie, AU - Pomel,Sébastien, AU - Diez-Martinez,Alba, AU - Ramiandrasoa,Florence, AU - Krauth-Siegel,R Luise, AU - Pethe,Stéphanie, AU - Blonski,Casimir, AU - Labruère,Raphaël, AU - Loiseau,Philippe M, Y1 - 2016/10/12/ PY - 2016/07/04/received PY - 2016/09/20/revised PY - 2016/10/10/accepted PY - 2016/10/30/pubmed PY - 2017/7/27/medline PY - 2016/10/30/entrez KW - Antikinetoplastids KW - Benzotriazole KW - Leishmania donovani KW - Polyamines KW - Trypanosoma brucei KW - Trypanothione reductase SP - 84 EP - 90 JF - Bioorganic & medicinal chemistry JO - Bioorg Med Chem VL - 25 IS - 1 N2 - 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/27793448/Synthesis_and_in_vitro_antikinetoplastid_activity_of_polyamine_hydroxybenzotriazole_conjugates_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(16)30942-7 DB - PRIME DP - Unbound Medicine ER -