“…Notwithstanding, for natural (poly)phenols that do pass that stage, there are strong hints that C -glucosylation should be considered when it comes to the pursuit of non-reactive lipophilic (poly)phenols with antidiabetic properties: (1) C -glucosides extracted from natural plant sources are increasingly recognized as functional ingredients for their potent antihyperglycaemic, anti-aggregation, and antioxidant bioactivities, both alone or in combination with other antidiabetic compounds [ 17 , 22 , 23 , 24 , 25 , 26 ]; (2) sugar-linked compounds may exhibit improved toxicity, solubility, and membrane permeability profiles versus their aglycones, which may enhance their bioavailability [ 27 , 28 , 29 ]; (3) when compared to O -glycosides, their (poly)phenol C -glucosyl analogs may also lead to improved selectivity and metabolic stability [ 17 , 30 ]; (4) as mentioned above, they seem to prevent membrane-disrupting effects of lipophilic (poly)phenol PAINS/IMPs [ 14 ]. Let us consider the successful case of gliflozins, a class of C -glucosyl aromatic compounds originally developed and approved as SGLT2 inhibitors for the treatment of type 2 diabetes [ 31 ]. The primary ancestor of gliflozins is the natural membrane dipole potential reducer phloretin, found in apples, pears, and other fruits [ 32 ].…”