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

doi:10.1021/acsmedchemlett.9b00218

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

ACS Med Chem Lett. 2019 Sep 9;11(3):278-285. doi: 10.1021/acsmedchemlett.9b00218. eCollection 2020 Mar 12.

Authors

Swapna Varghese¹, Raphaël Rahmani¹, Stephanie Russell², Girdhar Singh Deora¹, Lori Ferrins¹, Arthur Toynton², Amy Jones³, Melissa Sykes³, Albane Kessler⁴, Amanda Eufrásio⁵, Artur Torres Cordeiro⁵, Julian Sherman⁶, Ana Rodriguez⁶, Vicky M Avery³, Matthew J Piggott², Jonathan B Baell^{1

7

8

9}

Affiliations

¹ Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
² Chemistry, School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.
³ Discovery Biology, Griffith Institute for Drug Discovery, Griffith University, Don Young Road, Nathan, Queensland 4111, Australia.
⁴ GlaxoSmithKline, 28760 Tres Cantos, Spain.
⁵ Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials, Campinas, São Paulo 13083-970, Brazil.
⁶ Anti-Infectives Screening Core, New York University School of Medicine, New York 10016, United States.
⁷ School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211816, China.
⁸ ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria 3052, Australia.
⁹ Australian Translational Medicinal Chemistry Facility (ATMCF), Monash University, Parkville, Victoria 3052, Australia.

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.