Exploring the Potential of Isoindole‐1,3‐Dione Derivatives as Novel Inhibitors of Aldose Reductase: An <i>In Silico</i> and <i>In Vitro</i> Insight into Therapeutic Strategies for Diabetic Complications

Abstract This study explores the potential of isoindole‐1,3‐dione derivatives as novel inhibitors of aldose reductase (AR), focusing on their in silico and in vitro effects for therapeutic strategies against diabetic complications. Aldose reductase, a critical enzyme in the polyol pathway, plays a significant role in glucose metabolism and has been linked to diabetic complications. In this comprehensive study, isoindole‐1,3‐dione derivatives were synthesized and evaluated for their inhibitory effects on the recombinant human AR enzyme. The compounds’ inhibitory activities were measured both in vitro and through in silico techniques, employing molecular docking and free binding energy calculations and ADME studies. The newly synthesized compounds demonstrated varied inhibitory effects, with ethyl and phenyl substituents at specific positions enhancing inhibitory activity. Notably, compounds with carboxylic acid derivatives exhibited potent inhibitory effects, especially compound 6 with an IC 50 value of 1.649 μM. In conclusion, this study provides valuable insights into the inhibitory potential of isoindole‐1,3‐dione derivatives against AR, suggesting their potential therapeutic application in mitigating diabetic complications. The combination of experimental and computational approaches offers a comprehensive understanding of the compounds’ interaction mechanisms and pharmacokinetic profiles, supporting their further exploration as antidiabetic agents.