Abstract
Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder that is associated with the elderly. The current therapy that is used to treat AD is based mainly on the administration of acetylcholinesterase (AChE) inhibitors. Due to their low efficacy there is a considerable need for other therapeutic strategies. Considering that the malfunctions of different, but interconnected, biochemical complex pathways play an important role in the pathogenesis of this disease, a promising therapy may consist in administration of drugs that act on more than a target on biochemical scenery of AD. In this work, the synthesis and evaluation of xanthone and flavone derivatives as antioxidants with AChE inhibitory activity were accomplished. Among the obtained compounds, Mannich bases3and14showed capacity to inhibit AChE and antioxidant property, exerting dual activity. Moreover, for the most promising AChE inhibitors, docking studies on the target have been performed aiming to predict the binding mechanism. The results presented here may help to identify new xanthone and flavone derivatives as dual anti-Alzheimer agents with AChE inhibitory and antioxidant activities.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by progressive memory loss and cognitive deficits, being the most common form of dementia observed in the elderly [1, 2]
The synthesis of xanthones 1, 2, and 3 was achieved according to the general reaction pathway outlined in Scheme 1. 1,3,8-Trihydroxyxanthone (1) was obtained by one-step synthesis using two different approaches: Eaton’s reaction and Grover Shah and Shah (GSS) reaction
In the GSS reaction xanthone 1 was synthesized by the condensation of the same building blocks in the presence of zinc chloride in phosphorus oxychloride, instead of Eaton’s reagent [54] (Scheme 1)
Summary
AD is a neurodegenerative disorder that is characterized by progressive memory loss and cognitive deficits, being the most common form of dementia observed in the elderly [1, 2]. The pathogenesis of AD is not yet fully elucidated, the formation of senile plaques, the neurofibrillary tangles, loss of cholinergic neural transmission, and oxidative stress have been identified as the major characteristic hallmarks of this disease [1, 3, 4]. The current therapy for AD is based on the administration of AChE inhibitors, such as tacrine, rivastigmine, donepezil, and galantamine [1]. This therapeutic strategy only is capable of treating the symptoms of AD resulting in favoring of behavioral and cognitive improvements on AD patients [2]. Concerning this and that the number of cases of AD is increasing, it is urgent to find new effective therapeutic strategies for the treatment of AD [2, 5]
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