Aldose reductase (ALR2) is the
enzyme in charge of developing cellular toxicity caused by diabetic
hyperglycemia, which in turn leads to the generation of
reactive oxygen species triggering oxidative stress. Therefore, inhibiting ALR2 while pursuing a concomitant
anti-oxidant activity through dual-acting agents is now recognized as the gold standard treatment for preventing or at least delaying the progression of
diabetic complications. Herein we describe a novel series of (E)-
benzaldehyde O-benzyl
oximes 6a-e, 7a-e, 8a-e, and 9-11 as ALR2 inhibitors endowed with
anti-oxidant properties. Inspired by the natural products, the synthesized derivatives are characterized by a different polyhydroxy substitution pattern on their
benzaldehyde fragment, which proved crucial for both the
enzyme inhibitory activity and the
anti-oxidant capacity. Derivatives (E)-2,3,4-trihydroxybenzaldehyde O-(3-methoxybenzyl)
oxime (7b) and (E)-2,3,4-trihydroxybenzaldehyde O-(4-methoxybenzyl)
oxime (8b) turned out to be the most effective dual-acting products, proving to combine the best ALR2 inhibitory properties with significant
anti-oxidant efficacy.