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

Swapna Varghese, Raphael 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

Research output: Contribution to journalArticleResearchpeer-review

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
Number of pages8
JournalACS Medicinal Chemistry Letters
DOIs
Publication statusAccepted/In press - 2019

Keywords

  • Chagas disease
  • dual inhibitors
  • Human African trypanosomiasis
  • N-ethylurea pyrazole
  • neglected disease

Cite this

Varghese, Swapna ; Rahmani, Raphael ; Russell, Stephanie ; Deora, Girdhar Singh ; Ferrins, Lori ; Toynton, Arthur ; Jones, Amy ; Sykes, Melissa ; Kessler, Albane ; Eufrásio, Amanda ; Cordeiro, Artur Torres ; Sherman, Julian ; Rodriguez, Ana ; Avery, Vicky M. ; Piggott, Matthew J. ; Baell, Jonathan B. / Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi. In: ACS Medicinal Chemistry Letters. 2019.
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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.",
keywords = "Chagas disease, dual inhibitors, Human African trypanosomiasis, N-ethylurea pyrazole, neglected disease",
author = "Swapna Varghese and Raphael Rahmani and Stephanie Russell and Deora, {Girdhar Singh} and Lori Ferrins and Arthur Toynton and Amy Jones and Melissa Sykes and Albane Kessler and Amanda Eufr{\'a}sio and Cordeiro, {Artur Torres} and Julian Sherman and Ana Rodriguez and Avery, {Vicky M.} and Piggott, {Matthew J.} and Baell, {Jonathan B.}",
year = "2019",
doi = "10.1021/acsmedchemlett.9b00218",
language = "English",
journal = "ACS Medicinal Chemistry Letters",
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Varghese, S, Rahmani, R, Russell, S, Deora, GS, Ferrins, L, Toynton, A, Jones, A, Sykes, M, Kessler, A, Eufrásio, A, Cordeiro, AT, Sherman, J, Rodriguez, A, Avery, VM, Piggott, MJ & Baell, JB 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

Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi. / Varghese, Swapna; Rahmani, Raphael; Russell, Stephanie; Deora, Girdhar Singh; Ferrins, Lori; Toynton, Arthur; Jones, Amy; Sykes, Melissa; Kessler, Albane; Eufrásio, Amanda; Cordeiro, Artur Torres; Sherman, Julian; Rodriguez, Ana; Avery, Vicky M.; Piggott, Matthew J.; Baell, Jonathan B.

In: ACS Medicinal Chemistry Letters, 2019.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Varghese, Swapna

AU - Rahmani, Raphael

AU - Russell, Stephanie

AU - Deora, Girdhar Singh

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AU - Toynton, Arthur

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AU - Kessler, Albane

AU - Eufrásio, Amanda

AU - Cordeiro, Artur Torres

AU - Sherman, Julian

AU - Rodriguez, Ana

AU - Avery, Vicky M.

AU - Piggott, Matthew J.

AU - Baell, Jonathan B.

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