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Discovery of Potent N-Ethylurea Pyrazole Derivatives as Dual Inhibitors of Trypanosoma brucei and Trypanosoma cruzi. 2020
Swapna Varghese, and
Raphaël Rahmani, and
Stephanie Russell, and
Girdhar Singh Deora, and
Lori Ferrins, and
Arthur Toynton, and
Amy Jones, and
Melissa Sykes, and
Albane Kessler, and
Amanda Eufrásio, and
Artur Torres Cordeiro, and
Julian Sherman, and
Ana Rodriguez, and
Vicky M Avery, and
Matthew J Piggott, and
Jonathan B Baell
Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
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.
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