Isoindole‐1,3‐Dione Sulfonamides as Potent Inhibitors of Glucosidase, Aldose Reductase, and Tyrosinase: A Molecular Docking and Enzyme Inhibition Study

Diabetes mellitus, especially type 2, is a global health challenge, and effective enzyme inhibitors are essential for its control. Conventional inhibitors have drawbacks such as gastrointestinal side effects and regional availability, examples being acarbose and epalrestat. Moreover, tyrosinase, which controls melanin synthesis which is also a target for reducing hyperpigmentation disorders. In this study, we demonstrate the inhibitory action of novel isoindole-1,3-dione-based sulfonamides against key enzymes associated with diabetes and hyperpigmentation, α-Glucosidase (α-Glu), aldose reductase (ALR2), and tyrosinase. The presynthesized compounds (3, 4a-k) are tested for in vitro inhibition against α-Glu, ALR2, and tyrosinase and compared with reference compounds acarbose, epalrestat, and kojic acid. Kinetic studies showed that both competitive and noncompetitive inhibition modes were observed. Among them, compound 4a displayed the highest ALR2 inhibitory potency (K_i: 0.211 µM) and was superior to epalrestat. In terms of α-Glu, compound 4k was shown to be more potent with a K_i of 0.049 µM, particularly versus acarbose. Compound 4d showed excellent inhibitory activity (K_i: 1.43 µM) in tyrosinase assays, much more potent than kojic acid. Molecular docking studies revealed the details of enzyme-binding interactions, which justify the respective inhibitory mechanisms observed. Structure-activity relationships reflected that compounds with strong hydrogen bonding and hydrophobic interactions led to higher potency. These findings highlight the importance of isoindole-1,3-dione-based sulfonamides as therapeutic agents and will provide valuable leads for developing multifunctional enzyme inhibitors for such diabetic complications and hyperpigmentation.