Natural mimetic 4-benzyloxychalcones as potent pancreatic lipase inhibitors: Virtual screening, synthesis and biological evaluation

Abstract

Pancreatic lipase is a well-known target for obesity drug development. The inhibition of this enzyme mitigates the digestion and absorption of dietary fat. Despite some inconvenient side effects, orlistat is currently the only medication with FDA approval that works by inhibition of pancreatic lipase. Several natural flavonoids, including chalcones, have been reported to possess promising lipase inhibitory activity. In this paper, we describe the evaluation of the lipase inhibitory activity of our in-house natural mimetic chalcone library via virtual screening, followed by the synthesis and biological evaluation of the hits. Compound C82 showed low-micromolar activity against pancreatic lipase in vitro (IC 50 = 1.01 ± 0.86 µM). The interaction of C82 and lipase was additionally confirmed by a fluorescence quenching study. • Natural mimetic 4-benzyloxychalcone derivatives were identified as potential pancreatic lipase by computational methods. • Six 4-benzyloxychalcone derivatives were synthesized and evaluated for in vitro pancreatic lipase inhibitory activity. • Compound C82 showed low-micromolar activity • The interaction of compound C82 and pancreatic lipase was confirmed by a fluorescence quenching experiment.