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Exploring the multi-target performance of mitochondriotropic antioxidants against the pivotal Alzheimer’s disease pathophysiological hallmarks

dc.contributor.authorBenfeito S.
dc.contributor.authorFernandes C.
dc.contributor.authorVilar S.
dc.contributor.authorRemião F.
dc.contributor.authorUriarte E.
dc.contributor.authorBorges F.
dc.date.accessioned2020-09-02T22:13:05Z
dc.date.available2020-09-02T22:13:05Z
dc.date.issued2020
dc.identifier10.3390/molecules25020276
dc.identifier.citation25, 2, -
dc.identifier.issn14203049
dc.identifier.urihttps://hdl.handle.net/20.500.12728/3729
dc.descriptionAlzheimer 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. © 2020 by the authors.
dc.language.isoen
dc.publisherMDPI AG
dc.subjectAlzheimer disease
dc.subjectCholinesterase inhibitors
dc.subjectExcitotoxicity
dc.subjectIron accumulation
dc.subjectMitochondriotropic antioxidants
dc.subjectOxidative stress
dc.subjectβ-amyloid
dc.titleExploring the multi-target performance of mitochondriotropic antioxidants against the pivotal Alzheimer’s disease pathophysiological hallmarks
dc.typeArticle


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