Synthesis, molecular modelling and pharmacological evaluation of novel indole-thiazolidinedione based hybrid analogues as potential pancreatic lipase inhibitors

A series of novel indole-thiazolidinedione hybrid analogues (7a to 7 u) were synthesised, characterised and evaluated for their potential Pancreatic Lipase (PL) inhibition. Amongst the screened analogues, 7r was found to be the most active PL inhibitor with an IC50 of 2.67 mu M. Furthermore, enzyme inhibition kinetics study revealed a competitive mode of inhibition by the analogues. This fact was confirmed via fluorescence spectroscopy which further suggested the presence of one binding site for the synthesized analogues. Molecular docking was performed using human PL (PDB ID: 1LPB) and were in agreement with the in vitro results (Pearson's r = 0.8355, p < 0.05). A molecular dynamics study (100 ns) indicated that 7r was stable in a dynamic environment. The analogue 7r exhibited potential antioxidant activity and was devoid of cytotoxic effect on RAW 264.7 cells. Based on the in-vitro profiles, 7r was selected for the in-vivo pharmacological evaluation. Oral triglyceride tolerance test highlighted effect of 7r on the inhibition of triglyceride absorption. A four-week treatment of 7r in the HFD feed mice provided information regarding its anti-obesity effect with respect to parameters such as body weight, triglycerides, total cholesterol and high-density lipids. Quantification of the faecal triglyceride contents inveterates the potential role of 7r in the PL inhibition. Overall, the synthesized analogue 7r exerted an anti-obesity effect comparable to orlistat. All these results demonstrated the potential role of the newly synthesised indole-thiazolidinedione hybrid analogues in PL inhibition and may be studied further to find potential drug candidates for treating obesity.Communicated by Ramaswamy H. Sarma

Automated summary

A series of novel indole-thiazolidinedione hybrid analogues were synthesized and evaluated for their potential pancreatic lipase (PL) inhibition. Among them, 7r exhibited the highest activity with an IC50 of 2.67 μM. Enzyme inhibition kinetics study suggested a competitive mode of inhibition by the analogues, which was further confirmed by fluorescence spectroscopy. Molecular docking and molecular dynamics study supported the in vitro results. Moreover, 7r showed potential antioxidant activity and no cytotoxic effect on RAW 264.7 cells. In vivo pharmacological evaluation demonstrated the anti-obesity effect of 7r. Overall, the synthesized analogue 7r exerted a comparable anti-obesity effect to orlistat.