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Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum
Author(s) -
Teixeira de Moraes Gomes Paulo André,
Veríssimo de Oliveira Cardoso Marcos,
Santos Ignes Regina,
Amaro de Sousa Fabiano,
Conceição Juliana Maria,
Gouveia de Melo Silva Vanessa,
Duarte Denise,
Pereira Raquel,
Oliveira Rafael,
Nogueira Fátima,
Alves Luiz Carlos,
Brayner Fabio André,
Silva Santos Aline Caroline,
Rêgo Alves Pereira Valéria,
Lima Leite Ana Cristina
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000331
Subject(s) - trypanosoma cruzi , benznidazole , chagas disease , phthalimides , plasmodium falciparum , biology , microbiology and biotechnology , thiazole , chemistry , virology , malaria , biochemistry , immunology , stereochemistry , parasite hosting , phthalimide , world wide web , computer science
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 (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.