Alzheimer’s Disease (AD) and other dementias are ranked by the WHO as the World’s 7^th leading cause of death. Aiming to respond to this international public health priority, the Carbohydrate Chemistry Group of CQE-IMS has been dedicated to uncovering the AD-modifying potential of carbohydrate-based molecules. In this communication, the rational design, synthesis, and biological evaluation of C-glucosyl flavone analogs with neuroprotective activity against H₂O₂- and Aβ-induced cell death are explored. Furthermore, based on the well-established role of the binding between PrP^C and Aβ oligomers (Aβo) for Tau hyperphosphorylation in the brain, the structural optimization process leading up to the discovery of N-methylpiperazinyl flavones and their C-glucosyl derivatives as protein-protein interaction inhibitors (PPII) against PrP^C-Aβo is also presented. Importantly, because many planar lipophilic polyphenols such as the ones we have developed are Pan-Assay Interference CompoundS (PAINS), we were also interested in clarifying their ability to alter cell membrane properties in a non-specific manner. Our results show, for the first time, that well-known membrane disruptors such as resveratrol and genistein cease to reduce the membrane dipole potential when linked to a glucosyl moiety through a C-C bond, suggesting that our C-glucosides should not raise concerns regarding membrane-related PAINS-type behavior. This communication ultimately highlights the promising neuroprotective and PPII activity of C-glucosyl flavones and corresponding aglycones in the context of AD, while exploring the role of the sugar moiety in favorably tuning aglycone bioactivity, cytotoxicity, and unspecific membrane-modifying effects.