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Pancreatic lipase is a digestive enzyme involved in the hydrolysis of dietary fats. Orlistat, a potent pancreatic lipase inhibitor, is widely prescribed for long-term obesity treatment. Nevertheless, orlistat is reported for severe adverse effects including hepatotoxicity and pancreatitis. In the present study, a novel series of 11 benzyloxy substituted indole glyoxylamides were designed, synthesized and evaluated for  in vitro  pancreatic lipase inhibitory activity. Three analogues,  10b ,  11b  and  11c , exhibited potent activity (IC 50  ≤ 2.5 µM), with  11b  exhibiting a potent IC 50  of 1.68 µM comparable to orlistat (IC 50  = 0.99 µM). Further,  11b  exhibited reversible competitive inhibition with an inhibitory constant value of 0.98 μM. Molecular docking of these analogues was in agreement with  in vitro  results, wherein the MolDock scores exhibited significant correlation with their inhibitory activity (Pearson’s  r  = 0.7122). A 50 ns molecular dynamics simulation of  11b- pancreatic lipase complex confirmed the role of extended alkyl interactions along with π-π stacking and π-cation interactions, in stabilizing the ligand (Maximum RMSD ≈ 3 Å) in the active site. Gastro-intestinal absorption and toxicity prediction of the three potent analogues highlighted the suitability of  11b  for  in vivo  experiments.  11b  at a dose of 20 mg/kg exhibited anti-obesity efficacy comparable to orlistat (10 mg/kg), wherein the serum triglycerides were found to be 94.95 and 83.85 mg/dL, respectively. Further, faecal triglyceride quantification indicated  11b  to act through pancreatic lipase inhibition similar to orlistat. The present study identified a novel pancreatic lipase inhibitory benzyloxy substituted bis(indolyl) glyoxylamide  11b,  with promising anti-obesity activity. Communicated by Ramaswamy H. Sarma

journal of biomolecular structure and dynamics

Synthesis, molecular modelling,  in vitro  and  in vivo  evaluation of conophylline inspired novel benzyloxy substituted indole glyoxylamides as potent pancreatic lipase inhibitors