CONICET | Buscador de Institutos y Recursos Humanos

In Trypanosoma cruzi, the etiological agent of Chagas disease, the uptake ofpolyamines constitutes a promising target to design specific inhibitors withtripanocidal effects, since it is essential for parasite survival. In a previous study, Ant4, a 9-anthracenylmethyl-putrescine conjugate, designed for cancer treatment, inhibited the polyamine transport in T. cruzi parasites and also presented a strong trypanocidal effect on trypomastigotes, the bloodstream stage of T. cruzi. Considering the effects of Ant4 in the parasite, and that is not approved for use in humans, in this work we proposed to identify, using in silico and in vitro strategies, trypanocidal drugs approved for the treatment of other diseases that have similar structure and activity to Ant4. Initially, we performed a similarity ligand-based virtual screening in the SWEETLEAD database containing world´s approved drugs and natural products, using Ant4 as reference molecule. Applying this strategy, four antipsychotic tricyclic drugs were identified to be used in experimental assays in T. cruzi parasites. Three of them; promazine, chlorpromazine and clomipramine, showed to be effective inhibitors of polyamine uptake in epimastigotes and trypomastigotes. The drugs also revealed a high trypanocidal activity against amastigotes (IC50 values of 3.8, 1.9 and 2.9 μM, respectively) and trypomastigotes (IC50 values of 3.4, 2.7 and 1.3 μM, respectively) while in epimastigotes the IC50 were significantly higher (34.7, 41.4 and 39.7 μM, respectively).Taking advantage of the intrinsic fluorescence signal of Ant4 and chlorpromazine, we demonstrated that both compounds are incorporated into the parasite, suggesting the existence of additional intracellular targets.In conclusion, these polyamine transport inhibitors are promising trypanocidaldrugs, in addition they are approved for use in humans, which could reducesignificantly the requirements for their possible applications in the treatment of Chagas disease.