Hit-to-Lead Optimization of Novel 2-alkylaminomethylquinoline Derivatives as Anti-Chagas Agents

G. C. MUSCIA; F. J. ROLDÁN PACHECO; S. ASÍS; G. BULDAIN; F. FRANK

EUROPEAN JOURNAL OF MEDICAL CHEMISTRY

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER

Año: 2020 vol. 186 p. 1 - 8

0223-5234

Chagas disease is one of the main neglected diseases in the world, being endemic in 21 countries of LatinAmerica. This disease has become a global health problem due to migration of infected people nonendemiccountries. Even though this disease affects millions of people, only two drugs are approvedfor its treatment, benznidazole and nifurtimox, and both have several limitations. We have previouslyreported the synthesis and biological activity against T. cruzi of polysubstituted quinolines analogous tonatural products. Herein, we present the synthesis of rationally-based novel analogous of this family ofcompounds. 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, presentingthe highest selectivity index. Apart from controlling in vivo the parasitemia levels, compound 10 was ableto 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 thisdisease.