Medicinal Chemistry, SAR, and Molecular Insights Into 2,4-Thiazolidinediones as Antidiabetic Agents (2020–2025)

The thiazolidinedione (TZD) scaffold has long been recognized for its pharmacological versatility, particularly in the treatment of metabolic and inflammatory disorders. Among its derivatives, 2,4-thiazolidinediones (2,4-TZDs) have emerged as a prominent class of antidiabetic agents with diverse molecular targets. While their role as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists is well established, recent studies have revealed additional therapeutic mechanisms, including inhibition of protein tyrosine phosphatase 1B (PTP-1B), α-amylase, α-glucosidase, and aldose reductase—each contributing to improved glucose regulation and diabetes management. Moreover, the rise of dual and multitarget inhibitors highlights the evolving therapeutic potential of 2,4-TZDs beyond conventional pathways. This review presents a comprehensive analysis of recent developments (2020–2025) in the medicinal chemistry, structure–activity relationships (SARs), and antidiabetic mechanisms of 2,4-TZDs. Key structural modifications and their influence on biological activity are critically evaluated, alongside updates on recent patent disclosures and ongoing clinical trials. By integrating medicinal chemistry insights with pharmacological data, this review aims to support the rational design of next-generation 2,4-TZD-based antidiabetic therapeutics.