Trypanosomatids are protozoan parasites responsible for leishmaniasis, Chagas disease and sleeping sickness. The design of new antitrypanosomatid drugs with trypanosomicidal and leishmanicidal activities is an effective perspective. The thiazolidinone ring is an important scaffold for several biological disorders. Herein, 4‐oxothiazolidine‐5‐acetic acids (1 a‐1 w) have been synthesized from respective thiosemicarbazone and maleic anhydride. Some of these 4‐oxothiazolidine‐5‐acetic acids were toxic for trypomastigotes without affecting macrophages viability. From this series, compounds 1 e (IC50=10 μM), 1 u (IC50=8.94 μM), 1 g (IC50=5.65 μM) and 1 w (14.06 μM) showed the best anti‐T. cruzi activity for trypomastigote form, while 1 e, 1 u and 1 g showed SI higher than benznidazole (BZD). Similarly, against epimastigote the compound 1 q (IC50epi= 4.70 μM) has been found more selective and most active than benznidazole. However, evaluation against T. cruzi revealed that most of the active compounds have a low inhibition profile and weak leishmanicidal activity. In silico data suggests a good drug‐likeness profile, high chemical stability and demonstrate the use of these compounds in the designing of new anti‐T. cruzi and anti‐Leishmanial drugs.

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Chagas and leishmaniasis are both neglected tropical diseases, whose inefficient therapies have made them remain the cause for millions of deaths worldwide.

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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 cruzi agents. Herein we present the synthesis of 24 phthalimido-thiosemicarbazones (3 ax) and 14 phthalimidothiazoles (4 an) 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 cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC 50 = 3.60 μM), 3 h (IC 50 = 3.75 μM), and 4 j (IC 50 = 4.48 μM), were more active than the control drug benznidazole (IC 50 = 14.6 μM). Overall, the phthalimido-thiosemicarbazone derivatives were more potent than phthalimido-thiazole derivatives against T. cruzi. Flow cytometry assay data showed that compound 4 j was able to induce necrosis and apoptosis in trypomastigotes. Analysis by scanning electron microscopy showed that T. cruzi trypomastigote cells treated with compounds 3 h, 3 t, and 4 j at 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-thiazoles 4 l (IC 50 = 1.2 μM), 4 m (IC 50 = 1.7 μM), and 4 n (IC 50 = 2.4 μM). Together, these data revealed that phthalimido derivatives possess a dual antiparasitic profile with potential effects against T. cruzi and lead-like characteristics.

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