Chagas disease (CD) is a neglected tropical disease caused by the parasite Trypanosoma cruzi [1]. About 6-7 million people are infected worldwide, mainly in Latin America [1]. Benznidazole and Nifurtimox are the only available drugs for this disease but the problems with those drugs are related to their variable antiparasitic activity, the undesired side effects and long treatment duration among others [2]. Therefore, there is a great need for the development of new, effective, safe and affordable drugs for the treatment of CD.In this context, our group is focused on identifying new agents to fight against CD. So, twenty new derivatives were synthetized and tested in epimastigote, amastigote and trypomastigote forms in three different T. cruzi strains (SN3, Arequipa and Tulahuen). The cytotoxicity was also determined to establish their selectivity index (SI). The lead compound showed in vitro SI ranging from 99 to 258 times higher than Benznidazol in the amastigote form and from 333 to 2810 in the trypomastigote form of the parasites. The tested compounds in the SOS/umu screening test were non-genotoxic, whereas the reference drugs showed genotoxicity in the tested conditions. Regarding the studies of their mechanism of action, it seems that this family could be inhibitors of the Fe-SOD exclusive antioxidant defense trypanosomatids.According to their in vitro biological activity and preliminary toxicological studies, four out of twenty derivatives were selected for an in vivo assay in a murine mice model. The in vivo acute model showed that the compounds decrease the parasitemia from the beginning of the treatment and parasites were not detected from day 25 post-infection. Moreover, none of the compounds showed reactivation after immunosuppression with the dose used with the reference drug (100 mg/kg) and the lead compounds showed no reactivation also at 50 mg/kg [3].Considering the in vivo results, three out of four derivatives were selected for their mutagenicity evaluation and were non-mutagenic in the Ames test. Moreover, the absorption, distribution, metabolism, and excretion (ADME)/Tox and Pharmacokinetic (PK) evaluations are ongoing and the results will be presented in this congress.

Chagas disease and Leishmaniasis are trypanosomatid diseases considered as neglected tropical diseases by the WHO. These diseases are caused by T. Cruzi and Leishmania spp. that affect hundreds of millions of people all over the world [1]. Although the number of people affected has decreased, these infections are still threatening to human life. Governmental and non-governmental organizations have proposed big challenges with the commitment to meet the needs of these patients. One of the most important challenges is the search for new, safe, effective and affordable drugs to combat these diseases as the current therapeutic arsenal is inadequate and insufficient [2].In this context, our research group has been working on the discovery of new Mannich base-type derivative compounds as promising molecules for new anti-trypanosomatid agents [3].Considering the target product profile of these diseases and the results found to date, we persist in the search of potentially trypanocidal compounds; therefore, thirty-three new derivatives have been synthesized by different, simple and cheap synthetic routes.All compounds have been tested in vitro against the epimastigote form in three different T. cruzi strains (SN3, Arequipa and Tulahuen) for Chagas disease and in the promastigote form in L. braziliensis, L. donovani and L. infantum. The cytotoxicity has also been determined using Vero and THP-1 mammalian cell lines to establish their selectivity index (SI). Subsequently, the activity of the selected compounds is being carried out in the intracellular forms of the parasites. The results obtained from this evaluation will be shown in this Symposium.Acknowledgments: R.P.-B. is indebted to the University of Navarra for a grant. R.M-E. is grateful for a