Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro.

Abstract

The identification of a new series of growth inhibitors of Trypanosoma brucei rhodesiense, causative agent of Human African Trypanosomiasis (HAT), is described. A selection of compounds from our in-house compound collection was screened in vitro against the parasite leading to the identification of compounds with nanomolar inhibition of T. brucei growth. Preliminary SAR on the hit compound led to the identification of compound 34 that shows low nanomolar parasite growth inhibition (T. brucei EC50 5 nM), is not cytotoxic (HeLa CC50 > 25,000 nM) and is selective over other parasites, such as Trypanosoma cruzi and Plasmodium falciparum (T. cruzi EC50 8120 nM, P. falciparum EC50 3624 nM).

• Authors: Federica Ferrigno, Ilaria Biancofiore, Savina Malancona, Simona Ponzi, Giacomo Paonessa, Rita Graziani, Alberto Bresciani, Nadia Gennari, Annalise Di Marco, Marcel Kaiser, Vincenzo Summa, Steven Harper, Jesus M Ontoria
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 28 Issue 23-24 Pg. 3689-3692 (12 15 2018) ISSN: 1464-3405 [Electronic] England
• PMID: 30482621 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Imidazoles
• Piperazines
• Trypanocidal Agents

Topics

• HeLa Cells
• Humans
• Imidazoles (chemistry, pharmacology)
• Malaria, Falciparum (drug therapy)
• Piperazines (chemistry, pharmacology)
• Plasmodium falciparum (drug effects)
• Structure-Activity Relationship
• Trypanocidal Agents (chemistry, pharmacology)
• Trypanosoma brucei brucei (drug effects, growth & development)
• Trypanosomiasis, African (drug therapy, parasitology)