Design, Synthesis, and Biological Evaluation of Novel Benzimidazole Derivatives as Potent Aldose Reductase Inhibitors: An Integrated Approach Combining Molecular Docking, Molecular Dynamics, and Experimental Validation

Introduction: Aldose reductase (ALR2) plays a key role in the polyol pathway by catalyzing the reduction of glucose to sorbitol. Under hyperglycemic conditions, overactivation of this pathway contributes to diabetic complications, such as neuropathy, retinopathy, and nephropathy. Selective inhibition of ALR2 is thus a promising strategy for managing these complications. This study aimed to design and optimize a new class of selective ALR2 inhibitors with potential antihyperglycemic activity, combining computational modeling, synthesis, and biological evaluation. Methods: Structural analogs were designed based on pharmacophoric features known to interact with the ALR2 active site. Molecular docking was performed using the crystal structure of ALR2 (PDB ID: 1US0) to evaluate binding affinity and interactions. Compounds with favorable docking profiles were synthesized, purified, and characterized using spectroscopic methods. Their ALR2 inhibitory activity was assessed in vitro. Selected compounds were further evaluated by molecular dynamics (MD) simulations to assess binding stability using RMSD and RMSF analyses. Results: All designed compounds showed significant binding affinity for ALR2. Compounds CPD-7, 9, 11, 12, 22, 27, 30, 31, 33, and 35 exhibited superior docking scores and selectivity. Among these, CPD-9 demonstrated the highest in vitro inhibitory activity, with an IC50 of 0.311±0.07. MD simulations confirmed the stability of the ligand–ALR2 complexes, with RMSD and RMSF values ranging from 0.5 Å to 2.5 Å. Discussion: This integrated approach identified CPD-9 as a potent and selective ALR2 inhibitor with strong binding stability, highlighting its potential for treating diabetic complications through targeted ALR2 inhibition. Conclusion: This study successfully identified and optimized a novel series of aldose reductase (ALR2) inhibitors with promising antihyperglycemic potential. Computational modeling and docking studies revealed strong binding interactions of the designed analogs with the ALR2 active site, while molecular dynamics simulations confirmed the stability of these complexes.