American trypanosomiasis, also known as Chagas’ disease, is a potentially life-threatening illness, which occurs in 21 countries of South and Central America. Its etiological agent is Trypanosoma cruzi, a flagellate protozoa, which is transmitted to humans and other mammals mostly by the bite of a blood-sucking triatomine bug. Chagas’ disease affects 20 million people in South America, other 25 million are at risk of acquiring the disease, and more than 10,000 persons die annually. To date, only two drugs, benznidazole and nifurtimox are available on the market to treat this disease. However, these compounds provide unsatisfactory results for the chronic form and suffer from considerable side effects. Discovery of new lead compounds is therefore a priority. According to WHO, plants represent the best source for obtaining a wide variety of innovative compounds and could benefit a large population. Waltheriones are quinoline alkaloids which have been previously isolated from Waltheria sp. (Cretton et al., 2014; Cretton et al., 2015; Cretton et al., 2016; Monteillier et al., 2017). Some of these alkaloids showed potent in vitro activity on the amastigote form of Trypanosoma cruzi. In collaboration with the University of Sussex, chemical synthesis and optimization of waltherione scaffolds are being developed. Further potential hit-to-lead development is carried out on these molecules in collaboration with DNDi.