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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	<i>Trypanosoma cruzi</i> pyrazole derivatives trypanocidal activity 3D culture model Organic chemistry QD241-441
Acceso en línea:	https://doaj.org/article/ec1603fd968f454a8a41d175cc547d0b
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spelling	oai:doaj.org-article:ec1603fd968f454a8a41d175cc547d0b2021-11-11T18:40:31ZStructural 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>10.3390/molecules262167421420-3049https://doaj.org/article/ec1603fd968f454a8a41d175cc547d0b2021-11-01T00:00:00Zhttps://www.mdpi.com/1420-3049/26/21/6742https://doaj.org/toc/1420-3049Chagas 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.Lorraine Martins Rocha OrlandoGuilherme Curty LechugaLeonardo da Silva LaraByanca Silva FerreiraCynthia Nathalia PereiraRafaela Corrêa SilvaMaurício Silva dos SantosMirian Claudia S. PereiraMDPI AGarticle<i>Trypanosoma cruzi</i>pyrazole derivativestrypanocidal activity3D culture modelOrganic chemistryQD241-441ENMolecules, Vol 26, Iss 6742, p 6742 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	<i>Trypanosoma cruzi</i> pyrazole derivatives trypanocidal activity 3D culture model Organic chemistry QD241-441
spellingShingle	<i>Trypanosoma cruzi</i> pyrazole derivatives trypanocidal activity 3D culture model Organic chemistry QD241-441 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>
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.
format	article
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
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_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_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_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>
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/ec1603fd968f454a8a41d175cc547d0b
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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>

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