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Being the most common form of dementia, Alzheimer’s disease (AD) currently affects over 46 million people worldwide.1 However, currently prescribed drugs for the management of AD mostly consist of acetylcholinesterase (AChE) or both AChE and butyrylcholinesterase (BChE) inhibitors that cause an increase in acetylcholine brain levels, but allow only temporary symptomatic relief. Despite continuous efforts over the past 30 years, no cure is possible with the drugs delivered to the market so far. Widely reported for their neuroprotective effects, natural flavonoids such as quercetin, apigenin and chrysin have the ability to decrease amyloid-β (Aβ)-induced neurotoxicity while reducing β-secretase-mediated amyloid precursor protein (APP) processing, improving cognitive function and memory retention in rodents.2-4 Due to the rather complex and multifactorial nature of AD, we envisage that the broad activity of flavonoids comes across as a desirable feature of new multitarget drug leads able to interfere with several pathological features at once, thus maximizing the chances of blocking neurodegenerative progression in an effective way. Preliminary assays conducted by our group have shown that flavones tend to be more effective in inhibiting the formation of Aβ1-42 amyloid fibrils than analogue flavanones or isoflavones. In particular, 3-hydroxyflavone quercetin displayed a remarkable anti-amyloidogenic effect, which encouraged us to synthesize flavone analogues with drug-like properties and to investigate the role of C-C linked glucose units, that stabilize amyloid polypeptides in their disaggregated state.5 Ultimately, it is our goal to disclose structural requirements for the anti-amyloidogenic and neuroprotective effects, and to find new blood brain barrier (BBB)-permeable molecules that combine key features of the flavone scaffold with the potential benefits of the sugar moiety. In this communication, we will present the synthesis of C-glycosylated and non-glycosylated flavone analogues with potential neuroprotective effects. Furthermore, given the known relationship between type 2 diabetes and AD, the utility of this type of compounds in type 2 diabetic patients with cognitive impairment will also be discussed.   References: [1] Prince M., Wimo A., Guerchet M., Ali G.C., Wu Y.T., Prina M. World Alzheimer’s Report 2015. [2] Sabogal-Guaqueta A.M., Munoz-Manco J.I., Ramirez-Pineda J.R., Lamprea-Rodeiguez M., Osorio E., Cardona-Gomez G.P. Neuropharmacology, 2015, 93, 134. [3] Zhao L. Wang J.L. Liu R., Li X.X., Li J.F., Zhang L. Molecules, 2013, 18(8), 9949. [4] Li. R. Zang A., Zhang L., Zhang H., Zhao L., Qi Z. Wang H. Neurol Sci, 2014, 35, 1527. [5] Ladiwala A.R.A, Mora-Pale, Lin C., Bale S.S., Fishman Z.S., Dordick J.S., Tessier P.M. ChemBioChem, 2011, 12(11), 1749.     Acknowledgements: The research leading to these results has received funding from the European Union's Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 612347. The authors also acknowledge “PERsonalised ICT supported Service for Independent Living and Active Ageing” (PERSSILAA), FP7-ICT-2013-10, GA. 610359 and Fundacao para a Ciencia e a Tecnologia for the support of the project MULTI/UID 0612/2013 and for the Ph.D. grant awarded to Ana M. Matos (SFRH/BD/93170/2013).

&lt;strong&gt;Design and synthesis of CNS-targeted drug-like flavonoid analogues with potential against Alzheimer&amp;rsquo;s disease and type 2 diabetes&lt;/strong&gt;