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
Affiliations
Lidia Ciccone
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Giovanni Petrarolo
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Francesca Barsuglia
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Carole Fruchart-Gaillard
Département Médicaments et Technologies pour la Santé (DMTS), Université Paris Saclay, Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agricolture, l’Alimentation et l’Environment (INRAE), SIMoS, 91191 Gif-sur-Yvette, France
Evelyne Cassar Lajeunesse
Département Médicaments et Technologies pour la Santé (DMTS), Université Paris Saclay, Commissariat à l’Énergie Atomique et aux Énergies Alternatives (CEA), Institut National de Recherche pour l’Agricolture, l’Alimentation et l’Environment (INRAE), SIMoS, 91191 Gif-sur-Yvette, France
Adeniyi T. Adewumi
Molecular Bio-Computation and Drug Design Laboratory, School of Health Science, Westville Campus, University of KwaZulu-Natal, Durban 4001, South Africa
Mahmoud E. S. Soliman
Molecular Bio-Computation and Drug Design Laboratory, School of Health Science, Westville Campus, University of KwaZulu-Natal, Durban 4001, South Africa
Concettina La Motta
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Elisabetta Orlandini
Centre for Instrumentation Sharing, University of Pisa (CISUP), Lungarno Pacinotti 43, 56126 Pisa, Italy
Susanna Nencetti
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
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.