TY - JOUR
T1 - Dual parasiticidal activities of phthalimides
T2 - synthesis and biological profile against Trypanosoma cruzi and Plasmodium falciparum
AU - Teixeira de Moraes Gomes, Paulo André
AU - Veríssimo de Oliveira Cardoso, Marcos
AU - dos Santos, Ignes Regina
AU - Amaro de Sousa, Fabiano
AU - da Conceição, Juliana Maria
AU - Gouveia de Melo Silva, Vanessa
AU - Duarte, Denise
AU - Pereira, Raquel
AU - Oliveira, Rafael
AU - Nogueira, Fátima
AU - Alves, Luiz Carlos
AU - Brayner, Fabio André
AU - da Silva Santos, Aline Caroline
AU - Rêgo Alves Pereira, Valéria
AU - Lima Leite, Ana Cristina
PY - 2020/11/18
Y1 - 2020/11/18
N2 - 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.
AB - 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.
KW - Phthalimide
KW - Plasmodium falciparum
KW - Thiazole
KW - Thiosemicarbazone
KW - Trypanosoma cruzi
UR - http://www.scopus.com/inward/record.url?scp=85092713842&partnerID=8YFLogxK
UR - https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.202000331
U2 - 10.1002/cmdc.202000331
DO - 10.1002/cmdc.202000331
M3 - Article
C2 - 32813331
AN - SCOPUS:85092713842
VL - 15
SP - 2164
EP - 2175
JO - Chemmedchem
JF - Chemmedchem
SN - 1860-7179
IS - 22
ER -