Design, Synthesis, Molecular Modelling and in Vitro Evaluation of Indolyl Ketohydrazide‐Hydrazone Analogs as Potential Pancreatic Lipase Inhibitors

Abstract

Inhibition of Pancreatic lipase (PL) is considered to be a promising target for management of obesity, owing to its crucial role in the digestion of dietary triglycerides. A series of 31 indolyl ketohydrazide‐hydrazone analogues (5aa‐cm) were designed, synthesized and evaluated for their PL inhibitory potential. The designed analogues were synthesized by condensation of indolyl oxoacetohydrazide with various substituted benzaldehydes. All the analogues showed PL inhibitory activity in the range of 4.13 – 48.35 µM, as compared with orlistat (0.86 ± 0.09 µM). The most potent analogue 5bi (IC50 = 4.13 ± 0.95 µM) was found to show a competitive type of inhibition with Ki value of 0.725 µM. Additionally, the molecular docking study proved the binding of analogue 5bi at the active site of PL (PDB ID: 1LPB) with MolDock score of ‐141.279 kcal/mol. Furthermore, the protein‐ligand complex of analogue 5bi was found to be stable in molecular dynamics simulation for 100 ns with RMSD of less than 3.2 and 4 Å for the protein and ligand, respectively. The current work hereby provides a basis for the potential role of indolyl ketohydrazide‐hydrazone analogues in PL inhibition and further optimization could result in the generation of new leads as anti‐obesity agents.