Alzheimer’s Disease (AD) is characterized by a progressive cholinergic neurotransmission imbalance, with a decrease of acetylcholinesterase (AChE) activity followed by a significant increase of butyrylcholinesterase (BChE) in the later AD stages. BChE activity is also crucial for the development of Aβ plaques, the main hallmarks of this pathology. Moreover, systemic copper dyshomeostasis alters neurotransmission leading to AD. In the search for structures targeting both events, a set of novel 6-benzamide purine nucleosides was synthesized, differing in glycone configuration and N⁷/N⁹ linkage to the purine. Their AChE/BChE inhibitory activity and metal ion chelating properties were evaluated. Selectivity for human BChE inhibition required N⁹-linked 6-deoxy-α-d-mannosylpurine structure, while all three tested β-d-derivatives appeared as non-selective inhibitors. The N⁹-linked l-nucleosides were cholinesterase inhibitors except the one embodying either the acetylated sugar or the N-benzyl-protected nucleobase. These findings highlight that sugar-enriched molecular entities can tune bioactivity and selectivity against cholinesterases. In addition, selective copper chelating properties over zinc, aluminum, and iron were found for the benzyl and acetyl-protected 6-deoxy-α-l-mannosyl N^9-linked purine nucleosides. Computational studies highlight molecular conformations and the chelating molecular site. The first dual target compounds were disclosed with the perspective of generating drug candidates by improving water solubility.

Resveratrol and methyl caffeate health-promoting role in chronic and degenerative diseases is well known, however, their efficiency is affected by their low bioavailability in humans due to poor water solubility. Since these compounds have a peculiar role in the inhibition of Aβ oligomeric cytotoxicity and thus reduction of neuronal cell death [1,2], we were encouraged to investigate a new approach to overcome these issues. We disclose herein the benefits discovered by coupling sugars to these polyphenols, aiming to improve compound polarity, facilitated by the presence of additional OH groups of the sugar moiety. A robust synthetic route was developed in order to couple 2-deoxyglycosides to these natural molecules- resveratrol and caffeic acid, using glycals as easily accessed glycosyl donors. The resveratrol 2-deoxyglycosides 1 and 2 are more effective at protecting neuronal cells from peroxide-induced cytotoxicity than resveratrol itself, and caffeic acid ester glycoside 3 was also highly active as neuroprotective agent. Compounds were not cytotoxic to neuroblastoma, intestinal or liver cells at all concentrations tested. Coefficient partition measurements (logD, pH=7.4) confirmed the moderate lipophilicity of these resveratrol glycosides, which log D values are typical of CNS drug and for BBB penetration. This work illustrates the benefits of coupling sugars to polyphenols, in particular deoxy sugars, to improve polyphenol bioactivity and physicochemical properties.