Synthesis of amide warhead containing coumarin derivatives as potential pancreatic lipase inhibitors: in silico and in vitro evaluation for obesity treatment

A series of coumarin-3-carboxamide analogues has been designed, synthesized and assessed for their ability to inhibit pancreatic lipase (PL). Amongst all the synthesized analogues 5q, 5k and 5c exhibited potential PL inhibition activity with IC50 values of 19.41, 21.30 and 24.90 mu M, respectively when compared to orlistat (IC50 = 0.97 mu M). Analogue 5q was found to inhibit PL with IC50 value of 19.41 mu M and in a competitive manner with an inhibition constant (K-i) of 10.386 mu M. Further, the docking study confirmed the interaction of analogue 5q (MolDock score of -113.845 kcal mol(-1)) with important active site amino acids, namely Phe 77, Arg 256, His 263, etc. The MolDock scores displayed a substantial association with their inhibitory activity (Pearson's r = 0.5139), which was consistent with the in vitro results for these analogues. In order to comprehend the stability of the protein-ligand complex (5q) in a dynamic environment, a molecular dynamics study (100 ns) was conducted, and the findings indicated that this complex was stable under dynamic conditions. Overall, our findings demonstrated that the synthesized coumarin-3-carboxamide analogues had the ability to inhibit PL.