Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks
Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain ne...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/2/276 |
| _version_ | 1818557887253839872 |
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| author | Sofia Benfeito Carlos Fernandes Santiago Vilar Fernando Remião Eugenio Uriarte Fernanda Borges |
| author_facet | Sofia Benfeito Carlos Fernandes Santiago Vilar Fernando Remião Eugenio Uriarte Fernanda Borges |
| author_sort | Sofia Benfeito |
| collection | DOAJ |
| description | Alzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar β-amyloid 1−42 (Aβ<sub>42</sub>), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA’s) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds <b>7</b> and <b>11</b> with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity. |
| first_indexed | 2024-12-14T00:05:35Z |
| format | Article |
| id | doaj.art-82fe629f759b455f9eaab12bcf6e0622 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-12-14T00:05:35Z |
| publishDate | 2020-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-82fe629f759b455f9eaab12bcf6e06222022-12-21T23:26:03ZengMDPI AGMolecules1420-30492020-01-0125227610.3390/molecules25020276molecules25020276Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological HallmarksSofia Benfeito0Carlos Fernandes1Santiago Vilar2Fernando Remião3Eugenio Uriarte4Fernanda Borges5CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021/1055, 4169-007 Porto, PortugalCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021/1055, 4169-007 Porto, PortugalDepartmento Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, SpainUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, PortugalDepartmento Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, SpainCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021/1055, 4169-007 Porto, PortugalAlzheimer disease (AD) is the most common neurodegenerative disease featuring progressive and degenerative neurological impairments resulting in memory loss and cognitive decline. The specific mechanisms underlying AD are still poorly understood, but it is suggested that a deficiency in the brain neurotransmitter acetylcholine, the deposition of insoluble aggregates of fibrillar β-amyloid 1−42 (Aβ<sub>42</sub>), and iron and glutamate accumulation play an important role in the disease progress. Despite the existence of approved cholinergic drugs, none of them demonstrated effectiveness in modifying disease progression. Accordingly, the development of new chemical entities acting on more than one target is attracting progressively more attention as they can tackle intricate network targets and modulate their effects. Within this endeavor, a series of mitochondriotropic antioxidants inspired on hydroxycinnamic (HCA’s) scaffold were synthesized, screened toward cholinesterases and evaluated as neuroprotectors in a differentiated human SH-SY5Y cell line. From the series, compounds <b>7</b> and <b>11</b> with a 10-carbon chain can be viewed as multi-target leads for the treatment of AD, as they act as dual and bifunctional cholinesterase inhibitors and prevent the neuronal damage caused by diverse aggressors related to protein misfolding and aggregation, iron accumulation and excitotoxicity.https://www.mdpi.com/1420-3049/25/2/276alzheimer diseasemitochondriotropic antioxidantscholinesterase inhibitorsoxidative stressβ-amyloidiron accumulationexcitotoxicity |
| spellingShingle | Sofia Benfeito Carlos Fernandes Santiago Vilar Fernando Remião Eugenio Uriarte Fernanda Borges Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks Molecules alzheimer disease mitochondriotropic antioxidants cholinesterase inhibitors oxidative stress β-amyloid iron accumulation excitotoxicity |
| title | Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks |
| title_full | Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks |
| title_fullStr | Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks |
| title_full_unstemmed | Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks |
| title_short | Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks |
| title_sort | exploring the multi target performance of mitochondriotropic antioxidants against the pivotal alzheimer s disease pathophysiological hallmarks |
| topic | alzheimer disease mitochondriotropic antioxidants cholinesterase inhibitors oxidative stress β-amyloid iron accumulation excitotoxicity |
| url | https://www.mdpi.com/1420-3049/25/2/276 |
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