Abstract
It is well-accepted that the endogenous antioxidant protection system progressively decays in elderly people, and that the oxidative stress contributes to different neurodegenerative disorders such as Alzheimer’s Diseases (AD). The lower incidence of AD in countries which feature the Mediterranean Diet was associated to the high consumption of extra virgin olive oil and its polyphenolic fraction, in particular hydroxytyrosol. The protective role of these bio-phenols against oxidative stress, suggested that we combine their antioxidant/free radical scavenging activity with donepezil, an active ingredient which has just been approved for the treatment of AD. Different synthetic strategies were tested to conjugate the two different synthons in good yields. Additionally, a nitro-hydroxytyrosol derivative was synthesized to extend the application to other neurodegeneration inflammatory models. Then, their bioactivity was measured in different chemical and biological tests on a human neuroblastoma cell line (SHSY-5Y). Remarkable results on cell viability and the regulation of the redox state of cells were obtained. All hybrids showed negligible cell death under 1 μM and are stable and non toxic. Reactive oxygen species (ROS) measurements showed that the nitro-hybrid was the more effective one at reducing the ROS amount to physiological values. Then, in light of the bio-metal hypothesis of diverse neurodegenerative disorders, we tested these new compounds on the chelation properties of redox-active metals. The nitro-hybrid was able to chelate all of the tested metal cations, suggesting that we propose it as potential lead compound for a new class of neuroprotective antioxidant agents.
Highlights
With longer life expectancies and aging thanks to the modern medical advances as well as social and environmental conditions, neurological disorders are increasing
During the last decades many reviews and papers have demonstrated the role of oxidative stress in the pathogenesis of these neurodegenerative diseases, and the administration of both natural and synthetic antioxidant molecules was studied in diverse clinical trials (Blesa et al, 2015; Kim et al, 2015; Ganguly et al, 2021)
The recent literature showed an important effect of different nitro-hydroxytyrosol derivatives on Parkinson’s disease (PD) inflammatory models, demonstrating that the antioxidant properties of the ortho-diphenol moiety could be extended with the right modifications (Gallardo et al, 2014)
Summary
With longer life expectancies and aging thanks to the modern medical advances as well as social and environmental conditions, neurological disorders are increasing. The production of free radicals like the reactive oxygen species (ROS) is counterbalanced by the antioxidant systems, but in pathological conditions, or elderly peoples, the antioxidant defenses are not still to balance the ROS formation anymore. For these reasons many efforts have been made to develop new drugs with antioxidant and scavenging activities In order to extend the cognitive effect of these donepezil derivatives, a nitrohydroxytyrosol (NO-HT) synthon was combined into the donepezil structure
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