Synthesis, Molecular Modelling, In Vitro and Pharmacological Evaluation of Coumarin Analogues as Potential...

A set of 38 analogues of coumarin carboxamide was synthesized, characterized and examined for their potential to inhibit pancreatic lipase (PL). Amongst the analogues, 7b was identified as the most potent PL inhibitor with an IC₅₀ of 1.3 µM. Analysis of enzyme inhibition kinetics demonstrated that 7b inhibited PL in a competitive manner. On the basis of its in vitro profiles, 7b was selected for the pharmacological evaluation. The oral triglyceride tolerance test revealed that 7b inhibited the absorption of triglyceride. The investigation of the anti-obesity effects of 7b on high-fat diet (HFD)-fed mice over a period of 4 weeks yielded data on various parameters, including body weight, triglycerides, total cholesterol and high-density lipids. Through quantification of faecal triglyceride contents, the potential function of 7b in inhibiting PL is confirmed. The anti-obesity effect of the analogue 7b was similar to that of Orlistat. Molecular docking was conducted utilizing human PL (PDB ID: 1LPB), and the outcomes were correlated with in vitro (Pearson's r = 0.5). According to a molecular dynamics analysis (100 ns), 7b exhibited stability even in a dynamic environment. The aforementioned findings collectively indicate that the synthesized coumarin carboxamide analogues might play a role in inhibiting PL.