Advances in 5-Ene-2,4-thiazolidinediones Research: Multifaceted Biological Profile, Structure–Activity Relationship, and Mechanisms of Action

Recent advances in the chemistry of 5-ene-2,4-thiazolidinediones (5-ene-2,4-TZDs) has revealed their broad therapeutic potential, owing to their structural adaptability and ability to engage multiple biological targets. These compounds exhibit potent anti-inflammatory and antioxidant effects through both PPAR-γ- and Nrf2-independent mechanisms, alongside significant antibacterial and antifungal activity. Strategic N3 substitutions and hybrid pharmacophores have further enhanced their efficacy, particularly in treating inflammatory and infectious comorbidities. Importantly, the electrophilic nature of the 5-ene moiety may confer target promiscuity, enabling covalent interactions with nucleophilic residues in protein active sites. This review summarizes recent advances in the synthesis, pharmacological profiling, and SAR of 5-ene-2,4-TZDs, highlighting key molecular interactions with targets such as NF-κB and ROS modulators. By offering mechanistic insights and design strategies, this study provides a roadmap for developing next-generation 5-ene-2,4-TZDs with optimized activity and safety.