Exploring Isatin Derivatives as Multifunctional Antidiabetic Agents: Insights into α-Glucosidase and α-Amylase Inhibition.

Abstract

Diabetes mellitus, especially Type 2 Diabetes (T2DM), appears to be a worldwide health challenge marked by progressing hyperglycemia and related complications. Postprandial Hyperglycemia (PPHG) is a critical therapeutic target due to its strong link with cardiovascular risks. Inhibition of carbohydrate-hydrolysing enzymes, α-glucosidase and α-amylase, is an established strategy to mitigate PPHG. Current Inhibitors, including acarbose, miglitol, and voglibose, are effective but limited by gastrointestinal side effects. Isatin (1H-indole-2,3-dione) is a privileged scaffold in medicinal chemistry with diverse biological activities and modifiable sites (N-1, C-3, C-5), enabling optimisation for enzyme inhibition. A comprehensive literature search was conducted up to December 2025 using databases including Google Scholar, Web of Science, PubMed, traditional integrated knowledge resources, local dissertations, and books. The search employed keywords such as "α- glucosidase," "type 2 diabetes," "isatin scaffolds," "standard α-glucosidase enzyme inhibitors," and "isatin derivatives showing α-glucosidase and α-amylase inhibitory activity." This review compiles recent advances in isatin derivatives as potential α-glucosidase and α-amylase inhibitors, highlighting structure-activity relationships, synthetic strategies, including green chemistry and microwaveassisted synthesis, and dual inhibitory activity for improved efficacy and safety. Reported derivatives demonstrate remarkable potency, with some surpassing standard drugs in IC₅₀ values and docking scores, offering promising leads for next-generation antidiabetic therapeutics. Isatin derivatives show strong potential as multifunctional antidiabetic agents by effectively inhibiting α- glucosidase and α-amylase. Their structural versatility enables enhanced enzyme inhibition, supporting their promise as lead compounds for postprandial glucose control.