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Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization
[Image: see text] The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661480/ https://www.ncbi.nlm.nih.gov/pubmed/36318728 http://dx.doi.org/10.1021/acs.jmedchem.2c00817 |
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author | Cerqua, Ida Musella, Simona Peltner, Lukas Klaus D’Avino, Danilo Di Sarno, Veronica Granato, Elisabetta Vestuto, Vincenzo Di Matteo, Rita Pace, Simona Ciaglia, Tania Bilancia, Rossella Smaldone, Gerardina Di Matteo, Francesca Di Micco, Simone Bifulco, Giuseppe Pepe, Giacomo Basilicata, Manuela Giovanna Rodriquez, Manuela Gomez-Monterrey, Isabel M. Campiglia, Pietro Ostacolo, Carmine Roviezzo, Fiorentina Werz, Oliver Rossi, Antonietta Bertamino, Alessia |
author_facet | Cerqua, Ida Musella, Simona Peltner, Lukas Klaus D’Avino, Danilo Di Sarno, Veronica Granato, Elisabetta Vestuto, Vincenzo Di Matteo, Rita Pace, Simona Ciaglia, Tania Bilancia, Rossella Smaldone, Gerardina Di Matteo, Francesca Di Micco, Simone Bifulco, Giuseppe Pepe, Giacomo Basilicata, Manuela Giovanna Rodriquez, Manuela Gomez-Monterrey, Isabel M. Campiglia, Pietro Ostacolo, Carmine Roviezzo, Fiorentina Werz, Oliver Rossi, Antonietta Bertamino, Alessia |
author_sort | Cerqua, Ida |
collection | PubMed |
description | [Image: see text] The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC(50)s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents. |
format | Online Article Text |
id | pubmed-9661480 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-96614802022-11-15 Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization Cerqua, Ida Musella, Simona Peltner, Lukas Klaus D’Avino, Danilo Di Sarno, Veronica Granato, Elisabetta Vestuto, Vincenzo Di Matteo, Rita Pace, Simona Ciaglia, Tania Bilancia, Rossella Smaldone, Gerardina Di Matteo, Francesca Di Micco, Simone Bifulco, Giuseppe Pepe, Giacomo Basilicata, Manuela Giovanna Rodriquez, Manuela Gomez-Monterrey, Isabel M. Campiglia, Pietro Ostacolo, Carmine Roviezzo, Fiorentina Werz, Oliver Rossi, Antonietta Bertamino, Alessia J Med Chem [Image: see text] The design of multitarget drugs represents a promising strategy in medicinal chemistry and seems particularly suitable for the discovery of anti-inflammatory drugs. Here, we describe the identification of an indoline-based compound inhibiting both 5-lipoxygenase (5-LOX) and soluble epoxide hydrolase (sEH). In silico analysis of an in-house library identified nine compounds as potential 5-LOX inhibitors. Enzymatic and cellular assays revealed the indoline derivative 43 as a notable 5-LOX inhibitor, guiding the design of new analogues. These compounds underwent extensive in vitro investigation revealing dual 5-LOX/sEH inhibitors, with 73 showing the most promising activity (IC(50)s of 0.41 ± 0.01 and 0.43 ± 0.10 μM for 5-LOX and sEH, respectively). When challenged in vivo in zymosan-induced peritonitis and experimental asthma in mice, compound 73 showed remarkable anti-inflammatory efficacy. These results pave the way for the rational design of 5-LOX/sEH dual inhibitors and for further investigation of their potential use as anti-inflammatory agents. American Chemical Society 2022-11-01 2022-11-10 /pmc/articles/PMC9661480/ /pubmed/36318728 http://dx.doi.org/10.1021/acs.jmedchem.2c00817 Text en © 2022 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Cerqua, Ida Musella, Simona Peltner, Lukas Klaus D’Avino, Danilo Di Sarno, Veronica Granato, Elisabetta Vestuto, Vincenzo Di Matteo, Rita Pace, Simona Ciaglia, Tania Bilancia, Rossella Smaldone, Gerardina Di Matteo, Francesca Di Micco, Simone Bifulco, Giuseppe Pepe, Giacomo Basilicata, Manuela Giovanna Rodriquez, Manuela Gomez-Monterrey, Isabel M. Campiglia, Pietro Ostacolo, Carmine Roviezzo, Fiorentina Werz, Oliver Rossi, Antonietta Bertamino, Alessia Discovery and Optimization of Indoline-Based Compounds as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title | Discovery and
Optimization of Indoline-Based Compounds
as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title_full | Discovery and
Optimization of Indoline-Based Compounds
as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title_fullStr | Discovery and
Optimization of Indoline-Based Compounds
as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title_full_unstemmed | Discovery and
Optimization of Indoline-Based Compounds
as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title_short | Discovery and
Optimization of Indoline-Based Compounds
as Dual 5-LOX/sEH Inhibitors: In Vitro and In Vivo Anti-Inflammatory Characterization |
title_sort | discovery and
optimization of indoline-based compounds
as dual 5-lox/seh inhibitors: in vitro and in vivo anti-inflammatory characterization |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9661480/ https://www.ncbi.nlm.nih.gov/pubmed/36318728 http://dx.doi.org/10.1021/acs.jmedchem.2c00817 |
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