Design Synthesis Characterization and Biological Evaluation of Novel Pancreatic Lipase Inhibitors

Abstract

In the present study, some novel scaffolds of pancreatic lipase inhibitors were designed, synthesized and evaluated for their biological activity. A five point 3D QSAR pharmacophore model AAAHH was developed using a data set having 133 compounds. The developed pharmacophore consists of three hydrogen bond acceptor and two hydrophobic features. Pharmacophore based virtual screening identified five hit molecules that match with the pharmacophore sites as well as have the ability to bind with the PL enzyme. All the five hit molecules showed interaction with one of the amino acid residues present either in the catalytic triad or ion stabilizing residues of oxy anion hole: the regions that actively participate in the PL mediated lipolysis. The designed scaffold of phenacyl esters of N-substituted amino acids were synthesised by N-aroylation of amino acids and subsequent esterification with different phenacyl bromides in presence of N, N-Dimethylformamide (DMF). The synthesized compounds were characterized by IR, NMR and Mass spectroscopy, Simple, economic, scalable and reproducible method has been adopted for synthesising the lead molecules. The synthesised scaffolds of phenacyl esters of N-substituted amino acids were found to have better in vitro pancreatic lipase inhibitory activity (0.036-86 µg/ml) than N-alkyl phenacyl thiocarbamates (gt100 µg/ml). To understand the enzyme inhibition and to ensure the lead likeness. in silico docking and ADMET studies were carried on title compounds. All the compounds showed good interaction with pancreatic lipase. The nitro substituted compounds showed potency as well as less intestinal permeability which is one of the important pharmacokinetic parameters required for pancreatic lipase inhibitory activity. Novel phenacyl ester moiety has been designed for pancreatic lipase inhibitory activity and in this study it was found to be different from the standard drug orlistat with respect to basic moiety. molecular weight and ADME profile.