Design, synthesis and biological evaluation of mannich base-type derivatives as potential agents for the treatment of chagas disease

Résumé

Chagas disease is considered a neglected tropical disease that continues to endanger millions of people around the world. The current chemotherapy presents some disadvantages such as variable antiparasitic activity, undesired side effects and/or long treatment duration. Therefore, the development of new drugs is mandatory. Several studies suggest the Mannich base derivatives as an attractive scaffold for new antiparasitic agents. Our research group has developed new Mannich bases with promising antichagasic activity. In this context, we have designed and synthesized forty-five Mannich bases to be tested against the T. cruzi parasite. The structural modifications made for the design of new derivatives have been made in order to obtain more effective and less toxic potential candidates to combat this parasitic disease. The novel Mannich bases containing the ferrocenyl, phenethylamines, anilines or piperazines groups, among others, have been tested against three different T. cruzi strains and forms. The cytotoxicity on Vero cells was also evaluated to determine their selectivity index. According to potency and SI, the most promising compounds were selected to evaluate the genotoxicity capacity via SOS/umu-test. Once demonstrated that these compounds are non-genotoxic, two compounds were selected for in vivo study in BALB/c mice. After the in vivo test, the non-mutagenic capacity of the compound with the most promising antichagasic profile was evaluated by the Ames test. On the other hand, the possible mechanism of action of these compounds was studied through the alteration of excreted metabolites by the parasite during glucose metabolism, the detection of mitochondrial alterations and the inhibition of superoxide dismutase. Finally, computational studies were executed to propose the binding mode of the studied compounds to iron superoxide dismutase enzyme. The results obtained will allow us to promote further preclinical studies of the most promising compounds.