Structural Optimization and Biological Activity of Pyrazole Derivatives : Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi
Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, 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 T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 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-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:26 |
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| Enthalten in: |
Molecules (Basel, Switzerland) - 26(2021), 21 vom: 08. Nov. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Orlando, Lorraine Martins Rocha [VerfasserIn] |
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| Links: |
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| Themen: |
3D culture model |
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| Anmerkungen: |
Date Completed 03.12.2021 Date Revised 14.12.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.3390/molecules26216742 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM333089723 |
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| 100 | 1 | |a Orlando, Lorraine Martins Rocha |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Structural Optimization and Biological Activity of Pyrazole Derivatives |b Virtual Computational Analysis, Recovery Assay and 3D Culture Model as Potential Predictive Tools of Effectiveness against Trypanosoma cruzi |
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| 500 | |a Date Revised 14.12.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Chagas disease, a chronic and silent disease caused by Trypanosoma cruzi, 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 T. cruzi cysteine protease inhibitor. The in vitro phenotypic screening revealed compounds 3g, 3j, and 3m as promising candidates, with IC50 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-1H-pyrazole-imidazoline derivatives with the Br, Cl, and methyl substituents in the para-position. The 3m 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 3D culture model | |
| 650 | 4 | |a Trypanosoma cruzi | |
| 650 | 4 | |a pyrazole derivatives | |
| 650 | 4 | |a trypanocidal activity | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Trypanocidal Agents |2 NLM | |
| 700 | 1 | |a Lechuga, Guilherme Curty |e verfasserin |4 aut | |
| 700 | 1 | |a da Silva Lara, Leonardo |e verfasserin |4 aut | |
| 700 | 1 | |a Ferreira, Byanca Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Cynthia Nathalia |e verfasserin |4 aut | |
| 700 | 1 | |a Silva, Rafaela Corrêa |e verfasserin |4 aut | |
| 700 | 1 | |a Dos Santos, Maurício Silva |e verfasserin |4 aut | |
| 700 | 1 | |a Pereira, Mirian Claudia S |e verfasserin |4 aut | |
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