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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7587396 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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