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Article

Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks

1
CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, R. Campo Alegre 1021/1055, 4169-007 Porto, Portugal
2
Departmento Química Orgánica, Facultad de Farmacia, Universidad de Santiago de Compostela, Campus Vida, 15782 Santiago de Compostela, Spain
3
UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal
4
Instituto de Ciencias Químicas Aplicadas, Universidad Autonoma de Chile, Av. Libertador Bernardo O’Higgins, 7500912 Santiago de Chile, Chile
*
Authors to whom correspondence should be addressed.
Received: 22 November 2019 / Revised: 5 January 2020 / Accepted: 7 January 2020 / Published: 9 January 2020
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Enzyme Inhibitors)
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 (Aβ42), 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 7 and 11 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. View Full-Text
Keywords: Alzheimer disease; mitochondriotropic antioxidants; cholinesterase inhibitors; oxidative stress; β-amyloid; iron accumulation; excitotoxicity Alzheimer disease; mitochondriotropic antioxidants; cholinesterase inhibitors; oxidative stress; β-amyloid; iron accumulation; excitotoxicity
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MDPI and ACS Style

Benfeito, S.; Fernandes, C.; Vilar, S.; Remião, F.; Uriarte, E.; Borges, F. Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks. Molecules 2020, 25, 276. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020276

AMA Style

Benfeito S, Fernandes C, Vilar S, Remião F, Uriarte E, Borges F. Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks. Molecules. 2020; 25(2):276. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020276

Chicago/Turabian Style

Benfeito, Sofia, Carlos Fernandes, Santiago Vilar, Fernando Remião, Eugenio Uriarte, and Fernanda Borges. 2020. "Exploring the Multi-Target Performance of Mitochondriotropic Antioxidants against the Pivotal Alzheimer’s Disease Pathophysiological Hallmarks" Molecules 25, no. 2: 276. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules25020276

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