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Design, synthesis, evaluation, and molecular modeling studies of indolyl oxoacetamides as potential pancreatic lipase inhibitors.

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 µM, followed by 8c (IC50  = 5.12 µM), compared with the standard drug, orlistat (IC50  = 0.99 µM). 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 π-π stacking and π-cation interactions with the lid domain and Arg 256, respectively, in stabilizing the ligand at the active site (maximum observed root mean square deviation ≈ 2 Å). 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.