Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi

Swapna Varghese, Raphaël Rahmani, Stephanie Russell, Girdhar Singh Deora, Lori Ferrins, Arthur Toynton, Amy Jones, Melissa Sykes, Albane Kessler, Amanda Eufrásio, Artur Torres Cordeiro, Julian Sherman, Ana Rodriguez, Vicky M. Avery, Matthew J. Piggott, Jonathan B. Baell

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Abstract

Trypanosoma brucei (T. brucei) and Trypanosoma cruzi (T. cruzi) are causative agents of parasitic diseases known as human African trypanosomiasis and Chagas disease, respectively. Together, these diseases affect 68 million people around the world. Current treatments are unsatisfactory, frequently associated with intolerable side-effects, and generally inadequate in treating all stages of disease. In this paper, we report the discovery of N-ethylurea pyrazoles that potently and selectively inhibit the viability of T. brucei and T. cruzi. Sharp and logical SAR led to the identification of 54 as the best compound, with an in vitro IC50 of 9 nM and 16 nM against T. b. brucei and T. cruzi, respectively. Compound 54 demonstrates favorable physicochemical properties and was efficacious in a murine model of Chagas disease, leading to undetectable parasitemia within 6 days when CYP metabolism was inhibited.

Original languageEnglish
JournalACS Medicinal Chemistry Letters
DOIs
Publication statusPublished - 1 Jan 2019

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    Varghese, S., Rahmani, R., Russell, S., Deora, G. S., Ferrins, L., Toynton, A., Jones, A., Sykes, M., Kessler, A., Eufrásio, A., Cordeiro, A. T., Sherman, J., Rodriguez, A., Avery, V. M., Piggott, M. J., & Baell, J. B. (2019). Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi. ACS Medicinal Chemistry Letters. https://doi.org/10.1021/acsmedchemlett.9b00218