Novel 2,4-thiazolidinedione-quinoline hybrid molecules as REV-ERBα modulators for the treatment of diabetes mellitus

• Demonstrated the potential of quinoline-based thiazolidinedione derivatives as novel Rev-ErbA agonists for antidiabetic applications. • The integrated approach combining rational design, synthesis, in silico docking, and enzymatic inhibition assays has yielded promising results. • Fifteen novel quinoline-based thiazolidinedione derivatives were successfully synthesized. D • Docking studies against Rev-ErbA (PDB: 8d8i) revealed promising binding affinities for several analogs, suggesting potential Rev-ErbA agonism. • Enzymatic inhibition assays demonstrated significant α-amylase inhibitory activity (≥ 50% inhibition) for all derivatives, indicating their potential for carbohydrate digestion control. • Furthermore, structure-activity relationship (SAR) investigations were carried out to enhance the design and improve the inhibitory efficacy against both α-amylase and α-glucosidase. • The observed concentration-dependent α-glucosidase inhibition underscores the necessity for additional exploration to fine-tune molecular structures and maximize their therapeutic potential. • These findings warrant further exploration to confirm the Rev-ErbA agonist activity of promising analogs through cell-based assays. • This integrated strategy holds promise for advancing the design of innovative and effective antidiabetic agents that target the Rev-ErbA pathway. • Ultimately, this research has laid a robust groundwork for the development of quinoline-based thiazolidinedione derivatives as potent Rev-ErbA agonists, offering a promising therapeutic avenue for diabetes management. • The integrated approach, combining rational design, synthesis, in silico docking, and enzymatic inhibition assays, identified promising leads with significant α-amylase inhibitory activity. REV-ERBα, a nuclear receptor involved in circadian regulation of glucose and lipid metabolism, has emerged as a promising target for antidiabetic therapy. In this study, we report the design, synthesis, and dual-target biological evaluation of fifteen novel quinoline–thiazolidinedione (TZD) hybrids. These compounds were rationally designed using a pharmacophore hybridization approach to modulate REV-ERBα activity while simultaneously inhibiting key carbohydrate-metabolizing enzymes. Molecular docking studies were performed against the REV-ERBα ligand-binding domain (PDB: 8d8i), revealing favorable binding interactions for several analogs. To complement the nuclear receptor-focused analysis, all synthesized derivatives were assessed in vitro for their ability to inhibit α-amylase and α-glucosidase—enzymes directly involved in postprandial glucose regulation. Notably, the compounds exhibited significant enzyme inhibitory activity, with over 50% α-amylase inhibition across the series and concentration-dependent effects on α-glucosidase. This dual-target evaluation highlights the potential of these hybrid molecules as multifunctional antidiabetic agents, acting both through REV-ERBα modulation and enzymatic control of glycemic load.