Sridhar_2020_Arch.Pharm.(Weinheim)_353_e2000048

A series of indolyl oxoacetamide analogs was synthesized, characterized, and evaluated for their pancreatic lipase inhibitory activity using porcine pancreatic lipase (type II) and 4-nitrophenyl butyrate. Compound 8d exhibited a potent inhibition, with an IC50 value of 4.53 microM, followed by 8c (IC50 = 5.12 microM), compared with the standard drug, orlistat (IC50 = 0.99 microM). Furthermore, analogs 8c and 8d exhibited a reversible competitive inhibition, similar to orlistat. Molecular docking studies of the compounds 7a-f and 8a-f were in agreement with the in vitro results, wherein 8d exhibited a potential MolDock score of -163.052 kcal/mol. A 10-ns molecular dynamics simulation of 8d complexed with pancreatic lipase confirmed the role of pi-pi stacking and pi-cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation approximately 2 A). The present study led to the identification of novel indolyl oxoacetamides (8a-d) as potential pancreatic lipase inhibitory leads that might further result in enhanced potency through lead optimization.