Discovery of 2-(1H-imidazo-2-yl)piperazines as a new class of potent and non-cytotoxic inhibitors of Trypanosoma brucei growth in vitro. Issue 23 (15th December 2018)

• Record Type: Journal Article
• Authors: Ferrigno, Federica; Biancofiore, Ilaria; Malancona, Savina; Ponzi, Simona; Paonessa, Giacomo; Graziani, Rita; Bresciani, Alberto; Gennari, Nadia; Di Marco, Annalise; Kaiser, Marcel; Summa, Vincenzo; Harper, Steven; Ontoria, Jesus M.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 23/24(2018)
• Page Start: 3689
• Page End: 3692
• Publication Date: 2018-12-15
• Subjects: Trypanosoma brucei -- Sleeping sickness -- Human African Trypanosomiasis (HAT) -- Antiparasitic -- 2-(1H-imidazo-2-yl)piperazines; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.10.028
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: New safe and effective treatments for Human African Trypanosomiasis (HAT) are needed. An HTS campaign identified a novel series of Trypanosoma brucei growth inhibitors. Lead optimization generated nanomolar and non-cytotoxic T. brucei growth inhibitors. The compounds are selective over other parasites ( T. cruzi and Plasmodium falciparum ). The mechanism behind their antiparasitic effect may be novel. 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 compound34 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).