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Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity

Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the bas...

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Autores principales: Tzara, Ariadni, Lambrinidis, George, Kourounakis, Angeliki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399014/
https://www.ncbi.nlm.nih.gov/pubmed/34443516
http://dx.doi.org/10.3390/molecules26164928
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author Tzara, Ariadni
Lambrinidis, George
Kourounakis, Angeliki
author_facet Tzara, Ariadni
Lambrinidis, George
Kourounakis, Angeliki
author_sort Tzara, Ariadni
collection PubMed
description Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1–17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases.
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spelling pubmed-83990142021-08-29 Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity Tzara, Ariadni Lambrinidis, George Kourounakis, Angeliki Molecules Article Oxidative stress and inflammation are two conditions that coexist in many multifactorial diseases such as atherosclerosis and neurodegeneration. Thus, the design of multifunctional compounds that can concurrently tackle two or more therapeutic targets is an appealing approach. In this study, the basic NSAID structure was fused with the antioxidant moieties 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHB), its reduced alcohol 3,5-di-tert-butyl- 4-hydroxybenzyl alcohol (BHBA), or 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid (Trolox), a hydrophilic analogue of α-tocopherol. Machine learning algorithms were utilized to validate the potential dual effect (anti-inflammatory and antioxidant) of the designed analogues. Derivatives 1–17 were synthesized by known esterification methods, with good to excellent yields, and were pharmacologically evaluated both in vitro and in vivo for their antioxidant and anti-inflammatory activity, whereas selected compounds were also tested in an in vivo hyperlipidemia protocol. Furthermore, the activity/binding affinity of the new compounds for lipoxygenase-3 (LOX-3) was studied not only in vitro but also via molecular docking simulations. Experimental results demonstrated that the antioxidant and anti-inflammatory activities of the new fused molecules were increased compared to the parent molecules, while molecular docking simulations validated the improved activity and revealed the binding mode of the most potent inhibitors. The purpose of their design was justified by providing a potentially safer and more efficient therapeutic approach for multifactorial diseases. MDPI 2021-08-14 /pmc/articles/PMC8399014/ /pubmed/34443516 http://dx.doi.org/10.3390/molecules26164928 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tzara, Ariadni
Lambrinidis, George
Kourounakis, Angeliki
Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title_full Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title_fullStr Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title_full_unstemmed Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title_short Design of Multifaceted Antioxidants: Shifting towards Anti-Inflammatory and Antihyperlipidemic Activity
title_sort design of multifaceted antioxidants: shifting towards anti-inflammatory and antihyperlipidemic activity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399014/
https://www.ncbi.nlm.nih.gov/pubmed/34443516
http://dx.doi.org/10.3390/molecules26164928
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