New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi

Gomes, Paulo André Teixeira de Moraes; Barbosa, Míria de Oliveira; Santiago, Edna Farias; Cardoso, Marcos Veríssimo de Oliveira; Costa, Natáli Tereza Capistrano; Hernandes, Marcelo Zaldini; Moreira, Diogo Rodrigo Magalhães; Silva, Aline Caroline da; Santos, Thiago André Ramos dos; Pereira, Valéria Rêgo Alves; Santosd, Fábio André Brayner dos; Pereira, Glaécia Aparecida do Nascimento; Ferreira, Rafaela Salgado; Leite, Ana Cristina Lima

doi:10.1016/j.ejmech.2016.05.050

Cited by 51 publications

(22 citation statements)

References 42 publications

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“…However, analysis of the 1 H NMR spectra of the compounds indicated one predominant isomer; the E isomer by comparison with known analogues. [20] Intramolecular H-bonding involving the proton attached to N4 (in DMSO) with the imine N-atom leads to a distinctive singlet around 10.2 ppm, [20] and this is also seen here. Both thiosemicarbazones and respective 1,3-thiazoles were characterized by usual spectroscopy.…”

Section: Chemistrysupporting

confidence: 69%

“…Indeed, hydrazine double-bond C2=N2 is commonly assigned as E configuration. [20,23,[25][26][27][28] Concerning the exocyclic double-bond N3=C3, we suggest that the predominant configuration is in Z configuration. [20,23,[28][29][30] Besides, a representative 1 H-NMR spectrum of compound 4 n is presented in Supplementary Material ( Figure S1).…”

Section: Chemistrymentioning

confidence: 99%

“…[13,14] Phthalimides, thiosemicarbazones, and 1,3-thiazoles nucleus have been used as platform types to obtains antiplasmodial and anti-T. cruzi agents. [15][16][17][18][19][20][21][22] Our research group has explored the pharmacological properties of phthalimide derivatives, and as a result, phthalimido-thiazole derivatives were identified as building blocks to promising anti-T. cruzi candidates. [23] Here we performed the synthesis of 24 phthalimidothiosemicarbazones, (3 a-x), and 14 phthalimido-thiazoles (4 an) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

et al. 2020

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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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Section: Chemistrysupporting

confidence: 69%

Section: Chemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

et al. 2020

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“…One of the directions for the design of new antitrypanosomal agents using a molecular hybridization approach is the utilization of hydrazone fragments (Figure 9) as the linker group for the connection of the thiazole/4-thiazolidinone scaffold with the other molecular fragments [117,[141][142][143][144][145][146][147].…”

Section: -Thiazolidinone Frame In the Design Of Antitrypanosomalsmentioning

confidence: 99%

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Kryshchyshyn¹,

Kaminskyy²,

Grellier³

et al. 2021

Azoles - Synthesis, Properties, Applications and Perspectives

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Human African trypanosomiasis (HAT) and Chagas disease are neglected tropical diseases (NTDs) due to parasite protists from the Trypanosoma genus transmitted by insect vectors. Trypanosomiases affect mostly poor populations in the developing countries, and the development of new antitrypanosomal drugs is underinvested by governments and the pharmaceutical industry. In this chapter, we described the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments which exhibit good inhibition of trypanosome growth and might constitute potential candidates for the development of new drugs against trypanosomiasis. Antitrypanosomal design, mainly within structure-based design, led to the synthesis of 5-ene-4-thiazolidinone-3-alkanecarboxylic acids; 2,3-disubstituted 4-thiazolidinones; thiazolidinone-pyrazoline, phenylindole-thiazolidinone, and imidazothiadiazole-thiazolidinone hybrids; as well as 4-thiazolidinone-based fused heterocycles, especially thiopyrano[2,3-d]thiazoles, and non-thiazolidinone compounds-namely, isothiocoumarine derivatives. Moreover, antitrypanosomal 4-thiazolidinones are of special interest in the search for new antimalarial and antileishmanial agents. Also many active anticancer agents among the abovementioned 4-thiazolidinones have been discovered.

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“…To optimize the activity of a thiosemicarbazone derivative, a 1,3-thiazole core was used in the second study, leading to identification of a potent CRZ inhibitor. Utilizing electron microscopy, compound (1c) showed irreversible and specific morphological alterations [171] . Series of semicarbazone, thiosemicarbazone, and aminoguanidine derivatives were synthesized and investigated as CRZ inhibitors.…”

Section: Cysteine Protease Inhibitors (Cpis)mentioning

confidence: 99%

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (3): Kinetoplastids

Abaza

2019

Parasitologists United Journal

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Barreto [11] reviewed trypanosomatid PCD machinery pathway and presented a figure for the distribution of apoptotic or autophagic molecules in Leishmania spp., T. cruzi and T. brucei. Proteins associated with apoptosis (MCAs) were mainly demonstrated in trypanosomes, followed by L. donovani and L. infantum, and vice versa for proteins contributed in autophagy (ATGs) that were mainly assessed in L. major, followed by trypanosomes [11] .

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New 1,3-thiazole derivatives and their biological and ultrastructural effects on Trypanosoma cruzi

Cited by 51 publications

References 42 publications

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

Dual Parasiticidal Activities of Phthalimides: Synthesis and Biological Profile against Trypanosoma cruzi and Plasmodium falciparum

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Expression of cysteine proteinases and cystatins in parasites and use of cysteine proteinase inhibitors in parasitic diseases. Part III: Protozoa (3): Kinetoplastids

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