Abstract
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.
Highlights
Alzheimer disease (AD) is a progressive and degenerative neurological disorder resulting in memory loss and cognitive decline
The pathogenesis of AD has been linked to a deficiency in the brain neurotransmitter acetylcholine, a process that is related to the loss of memory and cognitive impairment observed in patients [1,2,3]
All the compounds placed the triphenylphosphonium cation in the bottom of the cavity and near the catalytic triad integrated by residues Ser198, Glu325 and His438, whereas the hydroxyphenyl
Summary
Alzheimer disease (AD) is a progressive and degenerative neurological disorder resulting in memory loss and cognitive decline. The pathogenesis of AD has been linked to a deficiency in the brain neurotransmitter acetylcholine, a process that is related to the loss of memory and cognitive impairment observed in patients [1,2,3]. One of the therapeutic strategies used to slow down the progression of AD symptoms is related to the enhancement of acetylcholine levels, throughthe inhibition of cholinesterases (ChE) located in cholinergic synaptic cleft areas [4,5,6]. Molecules 2019, 24, x cells, as well as in AD neuritic plaques and tangles [4,8].
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