Five years of research on 2,4-thiazolidinediones as anticancer agents: medicinal chemistry insights (2020-2024).

2,4-Thiazolidinediones (2,4-TZDs) are a class of heterocyclic compounds traditionally recognized for their antidiabetic activity, particularly as peroxisome proliferator-activated receptor gamma (PPARγ) agonists. However, in recent years, they have emerged as promising anticancer scaffolds due to their ability to influence key molecular pathways involved in tumorigenesis, including cell proliferation, apoptosis, angiogenesis, and metastasis. The structural flexibility of the 2,4-TZD core-especially at the C-5 position-makes it highly amenable to derivatization, offering opportunities to fine-tune bioactivity and selectivity. This review presents a focused evaluation of 2,4-TZD derivatives reported between 2020 and 2024, emphasizing structure-activity relationship (SAR) studies and their implications for anticancer drug design. We discuss how various substituent modifications influence cytotoxic potency and target selectivity. In addition, we explore the molecular mechanisms underlying the anticancer activity of selected 2,4-TZD derivatives, along with an overview of their pharmacological relevance. This compilation aims to serve as a valuable resource for medicinal chemists and drug discovery researchers working on next-generation 2,4-TZDs as targeted anticancer therapeutics.