Evaluation of Dihydropyridine Derivatives as Aldose Reductase Inhibitors: Enzymatic Screening, Molecular Docking and Ex Vivo Assessment of a Selected Compound in a Lens Model

Aldose reductase (AR) is a key enzyme in the polyol pathway and has been widely implicated in the development of diabetic complications, including cataract formation. In this work, a series of structurally modified 1,4-dihydropyridine (DHP) derivatives were evaluated as potential AR inhibitors. The compounds were obtained with high purity and subjected to enzymatic screening, exhibiting IC50 values ranging from 1.11 ± 0.07 to 55.34 ± 0.06 µM. The unsubstituted DHP scaffold exhibited intrinsic activity, whereas substitution at the 4-phenyl ring modulated inhibition in a nonlinear manner, reflecting the combined influence of steric and electronic factors on enzyme interactions. Kinetic analysis revealed mixed-type inhibition, indicating that the inhibitory behavior of the DHP derivatives cannot be explained solely by simple competition with the substrate. Molecular docking using the AR–NADP complex identified favorable binding poses and interactions with residues involved in ligand recognition and stabilization, although no direct correlation was observed between predicted docking scores and experimental inhibitory potency. A representative compound (DHP3, IC50 = 1.11 ± 0.07 µM) was elected for ex vivo evaluation in a rabbit lens model under hyperglycemic conditions. Treatment reduced glucose-induced lens opacity by 89.1%, estimated by image-based analysis, and decreased sorbitol accumulation by 57.48% relative to hyperglycemic control, indicating modulation of the polyol pathway at the tissue level. In contrast, no significant changes were detected in calcium content. These findings support the potential of DHP derivatives as a scaffold for aldose reductase inhibition and highlight their ability to attenuate early alterations associated with hyperglycemia in lens tissue. Further studies are required to expand biological validation and optimize their inhibitory profile.