Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Brand, S; Ko, EJ; Viayna, E; Thompson, S; Spinks, D; Thomas, M; Sandberg, L; Francisco, AF; Jayawardhana, S; Smith, VC; Jansen, C; De Rycker, M; Thomas, J; MacLean, L; Osuna-Cabello, M; Riley, J; Scullion, P; Stojanovski, L; Simeons, FRC; Epemolu, O; Shishikura, Y; Crouch, SD; Bakshi, TS; Nixon, CJ; Reid, IH; Hill, AP; Underwood, TZ; Hindley, SJ; Robinson, SA; Kelly, JM; Fiandor, JM; Wyatt, PG; Marco, M; Miles, TJ; Read, KD; Gilbert, IH; (2017) Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi. Journal of medicinal chemistry. ISSN 0022-2623 DOI:

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Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Public Health and Policy > Dept of Social and Environmental Health Research
Research Centre: Antimicrobial Resistance Centre (AMR)
PubMed ID: 28844141
Web of Science ID: 411171700006


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