Abstract
With the lack of available drugs able to prevent the progression of Alzheimer’s disease (AD), the discovery of new neuroprotective treatments able to rescue neurons from cell injury is presently a matter of extreme importance and urgency. Here, we were inspired by the widely reported potential of natural flavonoids to build a library of novel flavones, chromen-4-ones and their C-glucosyl derivatives, and to explore their ability as neuroprotective agents with suitable pharmacokinetic profiles. All compounds were firstly evaluated in a parallel artificial membrane permeability assay (PAMPA) to assess their effective permeability across biological membranes, namely the blood-brain barrier (BBB). With this test, we aimed not only at assessing if our candidates would be well-distributed, but also at rationalizing the influence of the sugar moiety on the physicochemical properties. To complement our analysis, logD7.4 was determined. From all screened compounds, the p-morpholinyl flavones stood out for their ability to fully rescue SH-SY5Y human neuroblastoma cells against both H2O2- and Aβ1-42-induced cell death. Cholinesterase inhibition was also evaluated, and modest inhibitory activities were found. This work highlights the potential of C-glucosylflavones as neuroprotective agents, and presents the p-morpholinyl C-glucosylflavone 37, which did not show any cytotoxicity towards HepG2 and Caco-2 cells at 100 μM, as a new lead structure for further development against AD.
Highlights
Alzheimer’s disease (AD) is a chronic neurodegenerative condition currently affecting more disease (AD) is a[1].chronic neurodegenerative affecting than Alzheimer’s40 million people worldwideAge, genetic background, condition and type 2currently diabetes (T2D)are more wellthan million people worldwide [1].Age, genetic background, and type diabetes (T2D)established risk factors for the development of this pathology, which leads to severe memory are well-established risk factors for the development of this pathology, which leads to severe impairment, language problems, extreme apathy, unpremeditated aggression, and delusional memory impairment, language problems, extreme apathy, unpremeditated aggression, and delusional symptoms [2]
Following the same synthetic route developed for chrysin (1) in a previous study [11], we were interested in the base-catalysed Claisen–Schmidt aldol condensation reaction for introducing structural diversity into the new flavone analogues
System (CNS)-MultiParameter Optimization (MPO) algorithm [22]. This mathematical tool enables the alignment of six key drug-like attributes: partition coefficient (ClogP), distribution coefficient (ClogD), acidity constant, molecular weight (MW), topological polar surface area (TPSA), and the number of hydrogen bond donors (HBD)
Summary
Alzheimer’s disease (AD) is a chronic neurodegenerative condition currently affecting more disease (AD) is a[1].chronic neurodegenerative affecting than Alzheimer’s40 million people worldwideAge, genetic background, condition and type 2currently diabetes (T2D)are more wellthan million people worldwide [1].Age, genetic background, and type diabetes (T2D)established risk factors for the development of this pathology, which leads to severe memory are well-established risk factors for the development of this pathology, which leads to severe impairment, language problems, extreme apathy, unpremeditated aggression, and delusional memory impairment, language problems, extreme apathy, unpremeditated aggression, and delusional symptoms [2]. Alzheimer’s disease (AD) is a chronic neurodegenerative condition currently affecting more disease (AD) is a[1]. Genetic background, condition and type 2currently diabetes (T2D). The loss of independence in the performance of the simplest tasks is a major stress symptoms [2]. TheAD losspatients, of independence inrelatives the performance of the simplest is a major stress factor and for and caregivers. With no factor only fortoAD patients, for relatives caregivers. With no drugs not being able stop disease but progression [3,4], theand hope and quality life for people living with drugs being able compromised to stop diseaseunless progression [3,4], the hope and life for people living with.
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