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New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition

A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton’s (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters’ ester lin...

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Autores principales: Chiasson, Audrey Isabel, Robichaud, Samuel, Ndongou Moutombi, Fanta J., Hébert, Mathieu P. A., Mbarik, Maroua, Surette, Marc E., Touaibia, Mohamed
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587396/
https://www.ncbi.nlm.nih.gov/pubmed/33066378
http://dx.doi.org/10.3390/molecules25204686
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author Chiasson, Audrey Isabel
Robichaud, Samuel
Ndongou Moutombi, Fanta J.
Hébert, Mathieu P. A.
Mbarik, Maroua
Surette, Marc E.
Touaibia, Mohamed
author_facet Chiasson, Audrey Isabel
Robichaud, Samuel
Ndongou Moutombi, Fanta J.
Hébert, Mathieu P. A.
Mbarik, Maroua
Surette, Marc E.
Touaibia, Mohamed
author_sort Chiasson, Audrey Isabel
collection PubMed
description A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton’s (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters’ ester linkage and phenolic acid moieties were investigated. Compound 28, bearing zileuton’s (1) benzo[b]thiophene and sinapic acid phenethyl ester’s (2) α,β-unsaturated phenolic acid moiety 28, was shown to be equipotent to zileuton (1), the only clinically approved 5-LO inhibitor, in stimulated HEK293 cells. Compound 28 was three times as active as zileuton (1) for the inhibition of 5-LO in PMNL. Compound 37, bearing the same sinapic acid (3,5-dimethoxy-4-hydroxy substitution) moiety as 28, combined with zileuton’s (1) hydroxyurea subunit was inactive. This result shows that the zileuton’s (1) benzo[b]thiophene moiety is essential for the inhibition of 5-LO product biosynthesis with our hydrids. Unlike zileuton (1), Compound 28 formed two π–π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π–π interaction with Phe177 which may play a part in product specificity as reported.
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spelling pubmed-75873962020-10-29 New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition Chiasson, Audrey Isabel Robichaud, Samuel Ndongou Moutombi, Fanta J. Hébert, Mathieu P. A. Mbarik, Maroua Surette, Marc E. Touaibia, Mohamed Molecules Article A novel series of zileuton-hydroxycinnamic acid hybrids were synthesized and screened as 5-lipoxygenase (5-LO) inhibitors in stimulated HEK293 cells and polymorphonuclear leukocytes (PMNL). Zileuton’s (1) benzo[b]thiophene and hydroxyurea subunits combined with hydroxycinnamic acid esters’ ester linkage and phenolic acid moieties were investigated. Compound 28, bearing zileuton’s (1) benzo[b]thiophene and sinapic acid phenethyl ester’s (2) α,β-unsaturated phenolic acid moiety 28, was shown to be equipotent to zileuton (1), the only clinically approved 5-LO inhibitor, in stimulated HEK293 cells. Compound 28 was three times as active as zileuton (1) for the inhibition of 5-LO in PMNL. Compound 37, bearing the same sinapic acid (3,5-dimethoxy-4-hydroxy substitution) moiety as 28, combined with zileuton’s (1) hydroxyurea subunit was inactive. This result shows that the zileuton’s (1) benzo[b]thiophene moiety is essential for the inhibition of 5-LO product biosynthesis with our hydrids. Unlike zileuton (1), Compound 28 formed two π–π interactions with Phe177 and Phe421 as predicted when docked into 5-LO. Compound 28 was the only docked ligand that showed a π–π interaction with Phe177 which may play a part in product specificity as reported. MDPI 2020-10-14 /pmc/articles/PMC7587396/ /pubmed/33066378 http://dx.doi.org/10.3390/molecules25204686 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chiasson, Audrey Isabel
Robichaud, Samuel
Ndongou Moutombi, Fanta J.
Hébert, Mathieu P. A.
Mbarik, Maroua
Surette, Marc E.
Touaibia, Mohamed
New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title_full New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title_fullStr New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title_full_unstemmed New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title_short New Zileuton-Hydroxycinnamic Acid Hybrids: Synthesis and Structure-Activity Relationship towards 5-Lipoxygenase Inhibition
title_sort new zileuton-hydroxycinnamic acid hybrids: synthesis and structure-activity relationship towards 5-lipoxygenase inhibition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587396/
https://www.ncbi.nlm.nih.gov/pubmed/33066378
http://dx.doi.org/10.3390/molecules25204686
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