Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile againstTrypanosoma cruziandPlasmodium falciparum

Chagas disease and malaria are two neglected tropical diseases (NTDs) that prevail in tropical and subtropical regions in 149 countries. Chagas is also present in Europe, the US and Australia due to immigration of asymptomatic infected individuals. In the absence of an effective vaccine, the control of both diseases relies on chemotherapy. However, the emergence of parasite drug resistance is rendering currently available drugs obsolete. Hence, it is crucial to develop new molecules. Phthalimides, thiosemicarbazones, and 1,3-thiazoles have been used as scaffolds to obtain antiplasmodial and anti-Trypanosoma cruziagents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 a-x) and 14 phthalimido-thiazoles (4 a-n) and the corresponding biological activity againstT. cruzi, Plasmodium falciparum, and cytotoxicity against mammalian cell lines. Some of these compounds showed potent inhibition ofT. cruziat low cytotoxic concentrations in RAW 264.7 cells. The most active compounds,3 t(IC50=3.60 mu M),3 h(IC50=3.75 mu M), and4 j(IC50=4.48 mu M), were more active than the control drug benznidazole (IC50=14.6 mu M). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives againstT. cruzi. Flow cytometry assay data showed that compound4 jwas able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed thatT. cruzitrypomastigote cells treated with compounds3 h,3 t, and4 jat IC(50)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 antimalarial activity were the phthalimido-thiazoles4 l(IC50=1.2 mu M),4 m(IC50=1.7 mu M), and4 n(IC50=2.4 mu M). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects againstT. cruziand lead-like characteristics.