Chagas disease is one of the main neglected diseases in the world, being endemic in 21 countries of Latin America. This disease has become a global health problem due to migration of infected people non-endemic countries. Even though this disease affects millions of people, only two drugs are approved for its treatment, benznidazole and nifurtimox, and both have several limitations. We have previously reported the synthesis and biological activity against T. cruzi of polysubstituted quinolines analogous to natural products. Herein, we present the synthesis of rationally-based novel analogous of this family of compounds. All the evaluated compounds presented trypanocidal activity. Three of them (6, 7 and 10) stand out for their selectivity indexes. Ethyl 2-((4-benzyl-1,4-diazepan-1-yl)methyl)-6-chloro-4-phenylquinoline-3-carboxylate (compound 10) was found to display anti-parasite activity, presenting the highest selectivity index. Apart from controlling in vivo the parasitemia levels, compound 10 was able to prevent tissue inflammation, a key factor to prevent the progression to chronic chagasic cardiomyopathy. The therapeutic effects of compound 10 are promising and suggest a new possibility to treat this disease.