Diabetes Mellitus, specifically type 2 diabetes mellitus (T2D), remains a serious global health challenge owing to the physiological changes linked with insulin resistance and hyperglycemia. It causes morbidity, mortality, and thereby financial burden on healthcare systems. Thiazolidinediones or glitazones, a decade-old, well-established pharmacophore, continue to play an important role in drug discovery as peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists, offering valuable insights into medicinal chemistry in terms of structure-activity relationships and therapeutic applications. This comprehensive review explores the biology of glitazones and their interactions with the PPAR-γ receptor, with a particular emphasis on their role in modulating glucose metabolism in T2D. Discussed the progression of glitazones from first- to third-generation, highlighting advances in selective PPAR-γ modulators (SPPAR-γMs) aimed to enhance efficacy and safety while minimizing adverse effects like fluid retention, weight gain, and cardiovascular risks. This review mainly focuses on medicinal chemistry, SAR/QSAR, molecular docking, and pharmacophore modelling and outlines the synthetic strategies for glitazones. Both conventional methods and the exploitation of natural substrates as bioisosteric replacements to enhance potency and safety profiles are explained. In addition to antidiabetic effects, glitazones are known to exhibit pleiotropic roles as anticancer, neuroprotective, anti-inflammatory, and hepatoprotective agents. Their therapeutic relevance extends to non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and polycystic ovary syndrome (PCOS) supported by recent clinical trials. This review also discusses limitations and toxicity, including the need for safer and more efficacious PPAR modulators. Overall, this review emphasizes the importance of glitazones in metabolic disease, highlights new breakthroughs, and identifies exciting new directions for drug discoveries.
