Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors
Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Chemistry |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fchem.2018.00126/full |
| _version_ | 1811196341214248960 |
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| author | Catarina Oliveira Fernando Cagide José Teixeira José Teixeira Ricardo Amorim Ricardo Amorim Lisa Sequeira Francesco Mesiti Tiago Silva Tiago Silva Jorge Garrido Jorge Garrido Fernando Remião Santiago Vilar Eugenio Uriarte Eugenio Uriarte Paulo J. Oliveira Fernanda Borges |
| author_facet | Catarina Oliveira Fernando Cagide José Teixeira José Teixeira Ricardo Amorim Ricardo Amorim Lisa Sequeira Francesco Mesiti Tiago Silva Tiago Silva Jorge Garrido Jorge Garrido Fernando Remião Santiago Vilar Eugenio Uriarte Eugenio Uriarte Paulo J. Oliveira Fernanda Borges |
| author_sort | Catarina Oliveira |
| collection | DOAJ |
| description | Alzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases. |
| first_indexed | 2024-04-12T00:57:44Z |
| format | Article |
| id | doaj.art-420a5a4aed444aff935b042fb4e8a4d3 |
| institution | Directory Open Access Journal |
| issn | 2296-2646 |
| language | English |
| last_indexed | 2024-04-12T00:57:44Z |
| publishDate | 2018-04-01 |
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| series | Frontiers in Chemistry |
| spelling | doaj.art-420a5a4aed444aff935b042fb4e8a4d32022-12-22T03:54:34ZengFrontiers Media S.A.Frontiers in Chemistry2296-26462018-04-01610.3389/fchem.2018.00126367329Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase InhibitorsCatarina Oliveira0Fernando Cagide1José Teixeira2José Teixeira3Ricardo Amorim4Ricardo Amorim5Lisa Sequeira6Francesco Mesiti7Tiago Silva8Tiago Silva9Jorge Garrido10Jorge Garrido11Fernando Remião12Santiago Vilar13Eugenio Uriarte14Eugenio Uriarte15Paulo J. Oliveira16Fernanda Borges17CIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalCNC, Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Cantanhede, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalCNC, Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Cantanhede, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalDepartment of “Scienze della Salute”, University “Magna Græcia” of Catanzaro, Catanzaro, ItalyCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalCNC, Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Cantanhede, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalDepartment of Chemical Engineering, School of Engineering (ISEP), Polytechnic of Porto, Porto, PortugalUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Porto, PortugalDepartamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, SpainDepartamento de Química Orgánica, Facultad de Farmacia, Universidade de Santiago de Compostela, Santiago de Compostela, SpainInstituto de Ciencias Químicas Aplicadas, Facultad de Ingeniería, Universidad Autónoma de Chile, Santiago, ChileCNC, Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Cantanhede, PortugalCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, PortugalAlzheimer's disease (AD) is a multifactorial age-related disease associated with oxidative stress (OS) and impaired cholinergic transmission. Accordingly, targeting mitochondrial OS and restoring cholinergic transmission can be an effective therapeutic strategy toward AD. Herein, we report for the first time dual-target hydroxybenzoic acid (HBAc) derivatives acting as mitochondriotropic antioxidants and cholinesterase (ChE) inhibitors. The studies were performed with two mitochondriotropic antioxidants AntiOxBEN1 (catechol derivative), and AntiOxBEN2 (pyrogallol derivative) and compounds 15–18, which have longer spacers. Compounds AntiOxBEN1 and 15, with a shorter carbon chain spacer (six- and eight-carbon) were shown to be potent antioxidants and BChE inhibitors (IC50 = 85 ± 5 and 106 ± 5 nM, respectively), while compounds 17 and 18 with a 10-carbon chain were more effective AChE inhibitors (IC50 = 7.7 ± 0.4 and 7.2 ± 0.5 μM, respectively). Interestingly, molecular modeling data pointed toward bifunctional ChEs inhibitors. The most promising ChE inhibitors acted by a non-competitive mechanism. In general, with exception of compounds 15 and 17, no cytotoxic effects were observed in differentiated human neuroblastoma (SH-SY5Y) and human hepatocarcinoma (HepG2) cells, while Aβ-induced cytotoxicity was significantly prevented by the new dual-target HBAc derivatives. Overall, due to its BChE selectivity, favorable toxicological profile, neuroprotective activity and drug-like properties, which suggested blood-brain barrier (BBB) permeability, the mitochondriotropic antioxidant AntiOxBEN1 is considered a valid lead candidate for the development of dual acting drugs for AD and other mitochondrial OS-related diseases.http://journal.frontiersin.org/article/10.3389/fchem.2018.00126/fullhydroxybenzoic acidsoxidative stressmitochondria-targeted antioxidantscholinesterase inhibitorsacetyl and butyrylcholinesterase |
| spellingShingle | Catarina Oliveira Fernando Cagide José Teixeira José Teixeira Ricardo Amorim Ricardo Amorim Lisa Sequeira Francesco Mesiti Tiago Silva Tiago Silva Jorge Garrido Jorge Garrido Fernando Remião Santiago Vilar Eugenio Uriarte Eugenio Uriarte Paulo J. Oliveira Fernanda Borges Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors Frontiers in Chemistry hydroxybenzoic acids oxidative stress mitochondria-targeted antioxidants cholinesterase inhibitors acetyl and butyrylcholinesterase |
| title | Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors |
| title_full | Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors |
| title_fullStr | Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors |
| title_full_unstemmed | Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors |
| title_short | Hydroxybenzoic Acid Derivatives as Dual-Target Ligands: Mitochondriotropic Antioxidants and Cholinesterase Inhibitors |
| title_sort | hydroxybenzoic acid derivatives as dual target ligands mitochondriotropic antioxidants and cholinesterase inhibitors |
| topic | hydroxybenzoic acids oxidative stress mitochondria-targeted antioxidants cholinesterase inhibitors acetyl and butyrylcholinesterase |
| url | http://journal.frontiersin.org/article/10.3389/fchem.2018.00126/full |
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