Exploring Thiazolidine-2,4-dione derivatives as privileged scaffolds for targeted anticancer agents: Biological activity and structure-activity relationship (SAR) insights

Cancer remains one of the most pressing global public health challenges. While chemotherapy has long been a cornerstone of cancer treatment, its inability to distinguish between cancerous and healthy cells often leads to significant toxicity and side effects. Over the past two decades, there has been a remarkable shift from these broad-spectrum cytotoxic drugs to more targeted therapies, which offer superior efficacy and a more favourable profile. Targeted treatments, unlike traditional chemotherapy, selectively attack cancer cells, and minimizing the side effect. However, a major obstacle with targeted therapies is the development of drug resistance, which continues to challenge the medical community's efforts to develop highly selective and low-toxicity anticancer drugs. In the quest for new anticancer agents that are both effective and have a favourable toxicity profile, heterocyclic compounds containing thiazolidinedione (TZD) derivatives have attracted significant attention in both preclinical and clinical research. TZDs can modulate multiple signalling pathways involved in cancer cell proliferation, apoptosis, and metastasis. The structural versatility of TZD compounds enables the development of derivatives with enhanced selectivity and potency against cancer cells. Beyond improving therapeutic efficacy and selectivity, TZD hybrid compounds hold the potential to overcome drug resistance. Over the past decade, several TZD-based hybrids have been developed and evaluated for their anticancer activity, with some showing promising in-vitro efficacy, indicating their potential as future anticancer agents. This study highlights the antitumor efficacy and potential mechanisms of action of these TZD hybrids and summarizes recent advancements in their development as promising anticancer drugs. Additionally, the study will explore the role of structure-activity relationship (SAR) studies in guiding the rational design of TZD hybrids to create more potent and selective candidates.