Biomolecules (Mar 2022)

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

  • Lidia Ciccone,
  • Giovanni Petrarolo,
  • Francesca Barsuglia,
  • Carole Fruchart-Gaillard,
  • Evelyne Cassar Lajeunesse,
  • Adeniyi T. Adewumi,
  • Mahmoud E. S. Soliman,
  • Concettina La Motta,
  • Elisabetta Orlandini,
  • Susanna Nencetti

DOI
https://doi.org/10.3390/biom12030448
Journal volume & issue
Vol. 12, no. 3
p. 448

Abstract

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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.

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