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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2022
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.
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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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