Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases
Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension o...
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doaj-7e4c8f8ec8cb43e691f140757bac9eea2021-02-24T00:03:47ZengMDPI AGAntioxidants2076-39212021-02-011032932910.3390/antiox10020329Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative DiseasesDaniel Chavarria0Ophelie Da Silva1Sofia Benfeito2Sandra Barreiro3Jorge Garrido4Fernando Cagide5Pedro Soares6Fernando Remião7Xavier Brazzolotto8Florian Nachon9Paulo J. Oliveira10José Dias11Fernanda Borges12CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, FranceCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, 4050-313 Porto, PortugalDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, FranceDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, FranceCNC—Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, 3060-197 Cantanhede, PortugalDépartement de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées, 91223 Brétigny-sur-Orge, FranceCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007 Porto, PortugalNeurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP<sup>+</sup>) conjugates (compounds <b>2</b>–<b>5</b>), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (<i>eq</i>BChE) and moderate electric eel acetylcholinesterase (<i>ee</i>AChE) inhibitors, with catechols 4 and 5 presenting lower IC<sub>50</sub> values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds <b>2</b>–<b>5</b> towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds <b>2–5</b> in complex with human ChEs (<i>h</i>ChEs) showed that these compounds exhibit different binging modes to <i>h</i>AChE and <i>h</i>BChE. Unlike AntiOXCINs, compounds <b>2–5</b> displayed moderate human monoamine oxidase (<i>h</i>MAO) inhibitory activity. Moreover, compounds <b>4</b> and <b>5</b> presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion.https://www.mdpi.com/2076-3921/10/2/329neurodegenerative diseasespiperinetriphenylphosphoniumcholinesterasesmonoamine oxidasemitochondria-targeted antioxidants |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel Chavarria Ophelie Da Silva Sofia Benfeito Sandra Barreiro Jorge Garrido Fernando Cagide Pedro Soares Fernando Remião Xavier Brazzolotto Florian Nachon Paulo J. Oliveira José Dias Fernanda Borges |
spellingShingle |
Daniel Chavarria Ophelie Da Silva Sofia Benfeito Sandra Barreiro Jorge Garrido Fernando Cagide Pedro Soares Fernando Remião Xavier Brazzolotto Florian Nachon Paulo J. Oliveira José Dias Fernanda Borges Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases Antioxidants neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
author_facet |
Daniel Chavarria Ophelie Da Silva Sofia Benfeito Sandra Barreiro Jorge Garrido Fernando Cagide Pedro Soares Fernando Remião Xavier Brazzolotto Florian Nachon Paulo J. Oliveira José Dias Fernanda Borges |
author_sort |
Daniel Chavarria |
title |
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
title_short |
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
title_full |
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
title_fullStr |
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
title_full_unstemmed |
Fine-Tuning the Biological Profile of Multitarget Mitochondriotropic Antioxidants for Neurodegenerative Diseases |
title_sort |
fine-tuning the biological profile of multitarget mitochondriotropic antioxidants for neurodegenerative diseases |
publisher |
MDPI AG |
series |
Antioxidants |
issn |
2076-3921 |
publishDate |
2021-02-01 |
description |
Neurotransmitter depletion and mitochondrial dysfunction are among the multiple pathological events that lead to neurodegeneration. Following our previous studies related with the development of multitarget mitochondriotropic antioxidants, this study aims to evaluate whether the π-system extension on the chemical scaffolds of AntiOXCIN2 and AntiOXCIN3 affects their bioactivity and safety profiles. After the synthesis of four triphenylphosphonium (TPP<sup>+</sup>) conjugates (compounds <b>2</b>–<b>5</b>), we evaluated their antioxidant properties and their effect on neurotransmitter-metabolizing enzymes. All compounds were potent equine butyrylcholinesterase (<i>eq</i>BChE) and moderate electric eel acetylcholinesterase (<i>ee</i>AChE) inhibitors, with catechols 4 and 5 presenting lower IC<sub>50</sub> values than AntiOXCIN2 and AntiOXCIN3, respectively. However, differences in the inhibition potency and selectivity of compounds <b>2</b>–<b>5</b> towards non-human and human cholinesterases (ChEs) were observed. Co-crystallization studies with compounds <b>2–5</b> in complex with human ChEs (<i>h</i>ChEs) showed that these compounds exhibit different binging modes to <i>h</i>AChE and <i>h</i>BChE. Unlike AntiOXCINs, compounds <b>2–5</b> displayed moderate human monoamine oxidase (<i>h</i>MAO) inhibitory activity. Moreover, compounds <b>4</b> and <b>5</b> presented higher ORAC-FL indexes and lower oxidation potential values than the corresponding AntiOXCINs. Catechols 4 and 5 exhibited broader safety windows in differentiated neuroblastoma cells than benzodioxole derivatives 2 and 3. Compound 4 is highlighted as a safe mitochondria-targeted antioxidant with dual ChE/MAO inhibitory activity. Overall, this work is a contribution for the development of dual therapeutic agents addressing both mitochondrial oxidative stress and neurotransmitter depletion. |
topic |
neurodegenerative diseases piperine triphenylphosphonium cholinesterases monoamine oxidase mitochondria-targeted antioxidants |
url |
https://www.mdpi.com/2076-3921/10/2/329 |
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