Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives
Chagas disease, caused by <i>Trypanosoma cruzi</i>, poses a significant public health challenge due to its widespread prevalence, limited therapeutic options, and adverse effects associated with available medications. In this study, we developed 13 novel pyrazole-imidazoline derivatives,...
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MDPI AG
2025-07-01
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| Online Access: | https://www.mdpi.com/1420-3049/30/15/3082 |
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| author | Edinaldo Castro de Oliveira Leonardo da Silva Lara Lorraine Martins Rocha Orlando Sarah da Costa Lanera Thamyris Perez de Souza Nathalia da Silva Figueiredo Vitoria Barbosa Paes Ana Carolina Mazzochi Pedro Henrique Myra Fernandes Maurício Silva dos Santos Mirian Claudia de Souza Pereira |
| author_facet | Edinaldo Castro de Oliveira Leonardo da Silva Lara Lorraine Martins Rocha Orlando Sarah da Costa Lanera Thamyris Perez de Souza Nathalia da Silva Figueiredo Vitoria Barbosa Paes Ana Carolina Mazzochi Pedro Henrique Myra Fernandes Maurício Silva dos Santos Mirian Claudia de Souza Pereira |
| author_sort | Edinaldo Castro de Oliveira |
| collection | DOAJ |
| description | Chagas disease, caused by <i>Trypanosoma cruzi</i>, poses a significant public health challenge due to its widespread prevalence, limited therapeutic options, and adverse effects associated with available medications. In this study, we developed 13 novel pyrazole-imidazoline derivatives, inspired by a previously identified cysteine protease inhibitor, and evaluated their antiparasitic activity. Our in silico analyses predicted favorable physicochemical profiles and promising oral bioavailability for these derivatives. Upon phenotypic screening, we observed that these new derivatives exhibited low cytotoxicity (CC<sub>50</sub> > 100 µM) and marked efficacy against intracellular amastigotes. Derivative <b>1k</b> showed high activity (IC<sub>50</sub> = 3.3 ± 0.2 µM), selectivity (SI = 73.9), and potency (pIC<sub>50</sub> = 5.4). In a 3D cardiac microtissue model, <b>1k</b> significantly reduced parasite load, matching the efficacy of benznidazole (Bz) even at lower concentrations. Both <b>1k</b> and Bz effectively prevented parasite recrudescence; however, neither resulted in parasite sterility under the experimental conditions employed. The combination of <b>1k</b>–Bz yielded an additive interaction, highlighting its potential for in vivo combination therapy. While structural changes abolished cysteine protease inhibition, incorporating a CF<sub>3</sub> substituent at the <i>para</i> position and excluding the amino group enhanced antiparasitic activity. These findings reinforce the promise of the pyrazole-imidazoline scaffold and support further structural optimizations to develop innovative candidates for treating Chagas disease. |
| format | Article |
| id | doaj-art-4b2d12401ac342ef9c26565bcf21a483 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-4b2d12401ac342ef9c26565bcf21a4832025-08-20T04:00:50ZengMDPI AGMolecules1420-30492025-07-013015308210.3390/molecules30153082Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline DerivativesEdinaldo Castro de Oliveira0Leonardo da Silva Lara1Lorraine Martins Rocha Orlando2Sarah da Costa Lanera3Thamyris Perez de Souza4Nathalia da Silva Figueiredo5Vitoria Barbosa Paes6Ana Carolina Mazzochi7Pedro Henrique Myra Fernandes8Maurício Silva dos Santos9Mirian Claudia de Souza Pereira10Laboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, Minas Gerais 37500-903, MG, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, Minas Gerais 37500-903, MG, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Avenida BPS, 1303, Pinheirinho, Itajubá, Minas Gerais 37500-903, MG, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365 Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilChagas disease, caused by <i>Trypanosoma cruzi</i>, poses a significant public health challenge due to its widespread prevalence, limited therapeutic options, and adverse effects associated with available medications. In this study, we developed 13 novel pyrazole-imidazoline derivatives, inspired by a previously identified cysteine protease inhibitor, and evaluated their antiparasitic activity. Our in silico analyses predicted favorable physicochemical profiles and promising oral bioavailability for these derivatives. Upon phenotypic screening, we observed that these new derivatives exhibited low cytotoxicity (CC<sub>50</sub> > 100 µM) and marked efficacy against intracellular amastigotes. Derivative <b>1k</b> showed high activity (IC<sub>50</sub> = 3.3 ± 0.2 µM), selectivity (SI = 73.9), and potency (pIC<sub>50</sub> = 5.4). In a 3D cardiac microtissue model, <b>1k</b> significantly reduced parasite load, matching the efficacy of benznidazole (Bz) even at lower concentrations. Both <b>1k</b> and Bz effectively prevented parasite recrudescence; however, neither resulted in parasite sterility under the experimental conditions employed. The combination of <b>1k</b>–Bz yielded an additive interaction, highlighting its potential for in vivo combination therapy. While structural changes abolished cysteine protease inhibition, incorporating a CF<sub>3</sub> substituent at the <i>para</i> position and excluding the amino group enhanced antiparasitic activity. These findings reinforce the promise of the pyrazole-imidazoline scaffold and support further structural optimizations to develop innovative candidates for treating Chagas disease.https://www.mdpi.com/1420-3049/30/15/3082<i>Trypanosoma cruzi</i>pyrazole-imidazoline3D culture modelchemotherapyChagas disease |
| spellingShingle | Edinaldo Castro de Oliveira Leonardo da Silva Lara Lorraine Martins Rocha Orlando Sarah da Costa Lanera Thamyris Perez de Souza Nathalia da Silva Figueiredo Vitoria Barbosa Paes Ana Carolina Mazzochi Pedro Henrique Myra Fernandes Maurício Silva dos Santos Mirian Claudia de Souza Pereira Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives Molecules <i>Trypanosoma cruzi</i> pyrazole-imidazoline 3D culture model chemotherapy Chagas disease |
| title | Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives |
| title_full | Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives |
| title_fullStr | Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives |
| title_full_unstemmed | Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives |
| title_short | Anti-<i>Trypanosoma cruzi</i> Potential of New Pyrazole-Imidazoline Derivatives |
| title_sort | anti i trypanosoma cruzi i potential of new pyrazole imidazoline derivatives |
| topic | <i>Trypanosoma cruzi</i> pyrazole-imidazoline 3D culture model chemotherapy Chagas disease |
| url | https://www.mdpi.com/1420-3049/30/15/3082 |
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