Dual Parasiticidal Activities of New Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum.

Phthalimides, thiosemicarbazones, and 1,3-thiazoles nucleus have been used as platform types to obtain antiplasmodial and anti-Trypanosoma cruzi agents. Here we present the synthesis of 24 phthalimido-thiosemicarbazones (3a-x) and 14 phthalimido-thiazoles (4a-n) and the corresponding biological activity against T. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition of T. cruzi at low cytotoxicity concentrations in RAW 264.7 cells. The most active compounds, 3t (IC50= 3.60 mM), 3h (IC50= 3.75mM), and 4j (IC50= 4.48 mM), were more active than the control drug Benznidazole (IC50= 14.6 mM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazoles derivatives against T. cruzi. Flow cytometry assay showed that compound 4j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with the compounds 3h, 3t, and 4j at IC50 concentrations, promoted changes in the shape, flagella, and surface of the parasite body similar to those observed in benznidazole-treated cells. The compounds with the highest antimalarials activity were the phthalimido-thiazoles 4l (IC50= 1.2mM), 4m (IC50= 1.7mM), and 4n (IC50= 2.4mM). Together, these data revealed, phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.