Abstract:
A series of 21 indolyl oxoacetamide analogues with benzyloxy-substituents were designed, synthesized and characterized using 1H NMR (Nuclear Magnetic Resonance), 13C NMR, and HRMS (High Resolution Mass Spectrometry) analysis. All the analogues were tested for inhibitory activity against pancreatic lipase. Two analogues, 9f and 10f, exhibited significant activity (IC50 of 2.89 and 2.50 µM, respectively), comparable to the standard drug, orlistat (IC50 = 0.99 µM). The potent analogues 10f and 9f exhibited significant binding affinity for pancreatic lipase (-170.222 kcal mol− 1 and − 153.547 kcal mol− 1). Additionally, both the potent analogues exhibited crucial interaction with Ser 152 and His 263 residues in the PL active site via hydrogen bonding. Molecular dynamics (MD) simulation was performed on the ligand-receptor complex of potent analogue (10f) for 200 ns. The molecule was stabilized by extending the π-π interactions with Phe 77 and Phe 215 of the active site lid domain due to benzyloxy substitution. Toxicity profile prediction indicated that all the analogues were non-hepatotoxic, unlike orlistat.