Design and Synthesis of Echitamine-inspired Hybrid Analogues Containing Thiazolidinediones as Potential Pancreatic Lipase Inhibitors

Background: Obesity is a multifactorial metabolic disease characterised by excessive accumulation of triglycerides. The prevalence and morbidity rates associated with obesity are increasing tremendously, posing a significant risk to society. Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary triglycerides; hence its inhibition is considered an attractive target in obesity. Methods: In this present work, a new series of echitamine-inspired indole-based thiazolidinedione hybrid analogues were designed, synthesized, and evaluated for their in vitro PL inhibitory potential. The nature of inhibition has been identified by enzyme kinetic analysis, whereas in silico molecular modelling tools (molecular docking and dynamic studies) were used for the identification of the mode of action at the catalytic site of PL (PDB ID: 1LPB). Fluorescence quenching was used for the identification of the interaction between the potent analogues with PL. Results: The condensation reaction of substituted indole derivatives with TZD in the presence of aqueous KOH resulted in the formation of the titled analogues. Analogues 7k and 7p displayed a potential PL inhibitory activity (IC50 = 11.36 and 11.87 mu M, respectively). A competitive mode of PL inhibition was revealed in the enzyme kinetic analysis. A static quenching mechanism was exhibited by the screened agents on PL. The obtained MolDock scores were aligned with the in vitro PL inhibitory activity (Pearson's r - 0.7575, p < 0.05). Moreover, the PL-ligand complexes were stable in the dynamic conditions. Conclusion: Analogue 7k exerted the potential activity, and further studies might result in novel lead molecules.