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 antioxidant 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.

Nature-Inspired O-Benzyl Oxime-Based Derivatives as New Dual-Acting Agents Targeting Aldose Reductase and Oxidative Stress

Ciccone, Lidia
Primo
;
Petrarolo, Giovanni;La Motta, Concettina
;
Orlandini, Elisabetta;Nencetti, Susanna
2022-01-01

Abstract

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 antioxidant 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.
2022
Ciccone, Lidia; Petrarolo, Giovanni; Barsuglia, Francesca; Fruchart-Gaillard, Carole; Cassar Lajeunesse, Evelyne; Adewumi, Adeniyi T; Soliman, Mahmoud E S; La Motta, Concettina; Orlandini, Elisabetta; Nencetti, Susanna
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11568/1155983
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