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

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 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.

Keywords: aldose reductase; aldose reductase inhibitors; anti-oxidants; benzaldehyde O-benzyl oximes; multifunctional compounds.

Figure 1

Representative examples of ARIs.

Scheme 1

Synthesis of the (E)-benzaldehyde O-benzyl oximes 6a–e, 7a–e, 8a–e, 9–11.

Figure 2

Effects of (E)-benzaldehyde O-benzyl oximes 6a–e, 7a–e, 8a–e, and 9–11, resveratrol, and pterostilbene on the production of thiobarbituric acid reactive substances (TBARS) in rat brain homogenate.

Figure 3

Radical scavenging capacity of (E)-benzaldehyde O-benzyl oximes 6b–d 7b–d, 8b–d, and resveratrol, expressed as a percentage of anti-oxidant activity (AA%).

Figure 4

(A) Structural view of 8b (working code FB6) bound to ALR2 enzyme active site. (B) Visual illustration of the ALR2-8b interaction network (color online). (C) Per-residue energy contributions to the ALR2-8b complex.

Figure 5

(A) Structural view of 6b (working code FB7) bound to ALR2 enzyme active site. (B) Visual illustration of the ALR2-6b interaction network (color online). (C) Per-residue energy contributions to the ALR2-6b complex.

Figure 6

(A) Structural view of 7b (working code FB8) bound to ALR2 enzyme active site. (B) Visual illustration of the ALR2-7b interaction network (color online). (C) Per-residue energy contributions to the ALR2-7b complex.

Figure 7

RMSD (A) and RMSF (B) plots for the unbound protein (black, working code AR–Apo), and the complex with 8b (red, working code AR-FB6), 6b (green, working code AR-FB7) and 7b (blue, working code AR-FB8). The structures C, D, and E are simulated ALR2-8b, ALR2-6b, ALR2-7b complexes at 200 ns superimposed with the ALR2–Apo system.

Figure 8

The radius of gyration, RoG (A), and the principal component analysis, PCA (B), illustrate the compactness and displaced inter-atoms of the ALR2 protein, respectively.

Figure 9

The MD simulation snapshots showed the loop structures at the time interval (ns) 1, 5, 50, 100, 150, and 200. Residues in the 218–228 region are enclosed in green and those in the 300–318 region are enclosed in blue circles.

Figure 10

Loop dynamics plot for residues 218–228 (A) and 300–318 (B). Zoomed-out snapshots of the loops A (C) and loop B (D). RMSF of the superimposed Apo and the bound ALR2 systems to show loop A (E) and loop B (F).

Figure 11

Solvent accessible surface area (SASA) plots of unbound protein (black, working code AR–Apo), and ALR2-8b (red, working code AR-FB6), ALR2-6b (green, working code AR-FB7), and ALR2-7b (blue, working code AR-FB8) systems.