Design, Synthesis and Antihyperglycemic/Antilipidemic Activities of Quinoline-thiazolidine-2,4-dione Hybrid

Background: Type 2 diabetes mellitus (T2DM) and hyperlipidemia are interrelated metabolic disorders that significantly increase cardiovascular risk. Thiazolidinediones are known insulin sensitizers, whereas quinoline derivatives possess diverse pharmacological activities. To explore their complementary activity, we designed a novel hybrid compound integrating a thiazolidinedione core with a quinoline moiety via a carbon spacer. Materials and Methods: The hybrid molecule was synthesized through a straightforward route and structurally confirmed by spectroscopic analyses. Zebrafish (Danio rerio) were employed as an in vivo model, with hyperglycemia induced by immersion in 100 mM glucose monohydrate for 12 days. Fish were divided into treatment groups receiving 20 or 80 mg/kg of the compound, alongside the controls. Biochemical parameters (glucose, triglycerides, insulin) and gene expression levels (NF-κB, ACOX1, ACCα) were assessed. In silico docking was conducted to predict molecular interactions. Results: Treatment with the hybrid compound significantly restored glucose, triglyceride, and insulin levels. High-dose administration suppressed NF-κB expression and normalized ACOX1 levels, while both low- and high-dose treatments downregulated ACCα compared with untreated hyperglycemic controls. Computational studies supported multitarget activity through predicted binding to PPAR-α and ACOX1. Conclusions: Quinoline-Thiazolidine-2,4-Dione demonstrated strong antihyperglycemic and antihypertriglyceridemic activities in zebrafish models, supported by in silico validation.