Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT.

Bioorganic & medicinal chemistry letters 2020 Jun 15

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A previous publication from our laboratory reported the identification of a new class of 2-(1H-imidazo-2-yl)piperazines as potent T. brucei growth inhibitors as potential treatment for Human African Trypanosomiasis (HAT). This work describes the structure-activity relationship (SAR) around the hit compound 1, which led to the identification of the optimized compound 18, a single digit nanomolar inhibitor (EC50 7 nM), not cytotoxic and with optimal in vivo profile that made it a suitable candidate for efficacy studies in a mouse model mimicking the second stage of disease. Copyright © 2020 Elsevier Ltd. All rights reserved.

Citation

Alina Ciammaichella, Federica Ferrigno, Andreina Basta, Melania D'Amico, Ilaria Biancofiore, Valentina Nardi, Simona Ponzi, Rita Graziani, Nadia Gennari, Maria Vittoria Orsale, Ivan Fini, Giacomo Paonessa, Vincenzo Summa, Steven Harper, Jesus M Ontoria. Optimization of 2-(1H-imidazo-2-yl)piperazines series of Trypanosoma brucei growth inhibitors as potential treatment for the second stage of HAT. Bioorganic & medicinal chemistry letters. 2020 Jun 15;30(12):127207