Varghese Swapna, Rahmani Raphaël, 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
Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
Chemistry, School of Molecular Sciences, The University of Western Australia, 35 Stirling Highway, Crawley, Perth, Western Australia 6009, Australia.
ACS Med Chem Lett. 2019 Sep 9;11(3):278-285. doi: 10.1021/acsmedchemlett.9b00218. eCollection 2020 Mar 12.
() and () 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 -ethylurea pyrazoles that potently and selectively inhibit the viability of and . Sharp and logical SAR led to the identification of as the best compound, with an IC of 9 nM and 16 nM against and , respectively. Compound 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.
（）和（）分别是被称为人类非洲锥虫病和恰加斯病的寄生虫病的病原体。这两种疾病加起来影响着全球6800万人。目前的治疗方法并不令人满意，常常伴有无法忍受的副作用，而且在治疗疾病的所有阶段通常都不够充分。在本文中，我们报告了乙基脲吡唑的发现，其能有效且选择性地抑制（）和（）的活力。清晰且合理的构效关系研究导致确定（）为最佳化合物，其对（）和（）的IC50分别为9 nM和16 nM。化合物（）表现出良好的物理化学性质，并且在恰加斯病的小鼠模型中有效，当细胞色素P450代谢被抑制时，在6天内导致无法检测到的寄生虫血症。
