Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum
| Autor: | Rafael Oliveira, Luiz Carlos Alves, Vanessa Gouveia de Melo Silva, Valéria Rêgo Alves Pereira, Fábio André Brayner, Denise Duarte, Marcos Veríssimo de Oliveira Cardoso, Ignes Regina Dos Santos, Raquel Pereira, Ana Cristina Lima Leite, Fabiano Amaro de Sousa, Paulo André Teixeira de Moraes Gomes, Aline Caroline da Silva Santos, Juliana Maria da Conceição, Fátima Nogueira |
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| Rok vydání: | 2020 |
| Předmět: |
Chagas disease
Antiparasitic medicine.drug_class Trypanosoma cruzi Plasmodium falciparum Phthalimides 01 natural sciences Biochemistry Microbiology Structure-Activity Relationship Parasitic Sensitivity Tests parasitic diseases Drug Discovery medicine Cytotoxic T cell General Pharmacology Toxicology and Pharmaceutics Cytotoxicity Pharmacology biology Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Chemistry Organic Chemistry Biological activity biology.organism_classification medicine.disease Trypanocidal Agents 0104 chemical sciences 010404 medicinal & biomolecular chemistry Benznidazole Molecular Medicine medicine.drug |
| Zdroj: | ChemMedChem. 15(22) |
| ISSN: | 1860-7187 |
| Popis: | 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 a-x) and 14 phthalimido-thiazoles (4 a-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 cytotoxic concentrations in RAW 264.7 cells. The most active compounds, 3 t (IC50 =3.60 μM), 3 h (IC50 =3.75 μM), and 4 j (IC50 =4.48 μM), were more active than the control drug benznidazole (IC50 =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 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 antimalarial activity were the phthalimido-thiazoles 4 l (IC50 =1.2 μM), 4 m (IC50 =1.7 μM), and 4 n (IC50 =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. |
| Databáze: | OpenAIRE |
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