Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum |
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| Authors: | Dr Paulo André Teixeira de Moraes Gomes Prof Marcos Veríssimo de Oliveira Cardoso Ignes Regina dos Santos Fabiano Amaro de Sousa Juliana Maria da Conceição Vanessa Gouveia de Melo Silva Denise Duarte Raquel Pereira Rafael Oliveira Prof Fátima Nogueira Dr Luiz Carlos Alves Dr Fabio André Brayner Dr Aline Caroline da Silva Santos Dr Valéria Rêgo Alves Pereira Prof Ana Cristina Lima Leite |
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| Affiliation: | 1. Departamento de Ciências Farmacêuticas Centro de Ciências da Saúde, Universidade Federal de Pernambuco, 50740-535 Recife, PE, Brazil;2. Laboratório de Prospecção de Moléculas Bioativas Programa de Pós-Graduação em Ciência e Tecnologia Ambiental para o Semiárido, Universidade de Pernambuco, 56328-903 Petrolina, PE, Brazil;3. Unidade de Ensino e Investigação de Parasitologia Médica, Global Health and Tropical Medicine, GHTM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, UNL, Rua da Junqueira no 100, 1349-008 Lisboa, Portugal;4. Laboratório de imunopatologia Keizo Asami (LIKA), Campus UFPE, 50670-901 Recife PE, Brazil
Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420 Recife, PE, Brazil;5. Instituto Aggeu Magalhães, Fundação Oswaldo Cruz, 50670-420 Recife, PE, Brazil |
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| Abstract: | 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. |
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| Keywords: | Phthalimide Plasmodium falciparum Thiazole Thiosemicarbazone Trypanosoma cruzi |
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