Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i>
Chagas disease, a chronic and silent disease caused by <i>Trypanosoma cruzi</i>, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The...
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MDPI AG
2021-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/26/21/6742 |
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| author | Lorraine Martins Rocha Orlando Guilherme Curty Lechuga Leonardo da Silva Lara Byanca Silva Ferreira Cynthia Nathalia Pereira Rafaela Corrêa Silva Maurício Silva dos Santos Mirian Claudia S. Pereira |
| author_facet | Lorraine Martins Rocha Orlando Guilherme Curty Lechuga Leonardo da Silva Lara Byanca Silva Ferreira Cynthia Nathalia Pereira Rafaela Corrêa Silva Maurício Silva dos Santos Mirian Claudia S. Pereira |
| author_sort | Lorraine Martins Rocha Orlando |
| collection | DOAJ |
| description | Chagas disease, a chronic and silent disease caused by <i>Trypanosoma cruzi</i>, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a <i>T. cruzi</i> cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds <b>3g</b>, <b>3j</b>, and <b>3m</b> as promising candidates, with IC<sub>50</sub> values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1<i>H</i>-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the <i>para</i>-position. The <b>3m</b> compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies. |
| first_indexed | 2024-03-10T05:55:22Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T05:55:22Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-ec1603fd968f454a8a41d175cc547d0b2023-11-22T21:25:54ZengMDPI AGMolecules1420-30492021-11-012621674210.3390/molecules26216742Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i>Lorraine Martins Rocha Orlando0Guilherme Curty Lechuga1Leonardo da Silva Lara2Byanca Silva Ferreira3Cynthia Nathalia Pereira4Rafaela Corrêa Silva5Maurício Silva dos Santos6Mirian Claudia S. Pereira7Laboratório 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, Av. BPS 1303, Pinheirinho, Itajubá 37500-903, MG, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Av. BPS 1303, Pinheirinho, Itajubá 37500-903, MG, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Av. BPS 1303, Pinheirinho, Itajubá 37500-903, MG, BrazilLaboratório de Síntese de Sistemas Heterocíclicos (LaSSH), Instituto de Física e Química (IFQ), Universidade Federal de Itajubá, Av. BPS 1303, Pinheirinho, Itajubá 37500-903, MG, BrazilLaboratório de Ultraestrutura Celular, Instituto Oswaldo Cruz, Fiocruz, Av. Brasil 4365, Manguinhos, Rio de Janeiro 21040-900, RJ, BrazilChagas disease, a chronic and silent disease caused by <i>Trypanosoma cruzi</i>, is currently a global public health problem. The treatment of this neglected disease relies on benznidazole and nifurtimox, two nitroheterocyclic drugs that show limited efficacy and severe side effects. The failure of potential drug candidates in Chagas disease clinical trials highlighted the urgent need to identify new effective chemical entities and more predictive tools to improve translational success in the drug development pipeline. In this study, we designed a small library of pyrazole derivatives (44 analogs) based on a hit compound, previously identified as a <i>T. cruzi</i> cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds <b>3g</b>, <b>3j</b>, and <b>3m</b> as promising candidates, with IC<sub>50</sub> values of 6.09 ± 0.52, 2.75 ± 0.62, and 3.58 ± 0.25 µM, respectively, against intracellular amastigotes. All pyrazole derivatives have good oral bioavailability prediction. The structure–activity relationship (SAR) analysis revealed increased potency of 1-aryl-1<i>H</i>-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the <i>para</i>-position. The <b>3m</b> compound stands out for its trypanocidal efficacy in 3D microtissue, which mimics tissue microarchitecture and physiology, and abolishment of parasite recrudescence in vitro. Our findings encourage the progression of the promising candidate for preclinical in vivo studies.https://www.mdpi.com/1420-3049/26/21/6742<i>Trypanosoma cruzi</i>pyrazole derivativestrypanocidal activity3D culture model |
| spellingShingle | Lorraine Martins Rocha Orlando Guilherme Curty Lechuga Leonardo da Silva Lara Byanca Silva Ferreira Cynthia Nathalia Pereira Rafaela Corrêa Silva Maurício Silva dos Santos Mirian Claudia S. Pereira Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> Molecules <i>Trypanosoma cruzi</i> pyrazole derivatives trypanocidal activity 3D culture model |
| title | Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> |
| title_full | Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> |
| title_fullStr | Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> |
| title_full_unstemmed | Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> |
| title_short | Structural Optimization and Biological Activity of Pyrazole Derivatives: Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against <i>Trypanosoma cruzi</i> |
| title_sort | structural optimization and biological activity of pyrazole derivatives virtual computational analysis recovery assay and 3d culture model as potential predictive tools of effectiveness against i trypanosoma cruzi i |
| topic | <i>Trypanosoma cruzi</i> pyrazole derivatives trypanocidal activity 3D culture model |
| url | https://www.mdpi.com/1420-3049/26/21/6742 |
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