Thi_2023_Bioorg.Med.Chem.Lett__129574

Aurone is a minor subgroup of flavonoids. Unlike other subgroups such as chalcone, flavone, and isoflavone, aurone has not been extensively explored as pancreatic lipase inhibitor. In this work, we studied the pancreatic lipase inhibitory potency of synthetic aurone derivatives. 36 compounds belonging to four series (4,6-dihydroxyaurones, 6-hydroxyaurones, 4,6-dialkoxyaurones, and 6 -alkoxyaurones) were designed and synthesized. Their in vitro inhibitory activities were determined by spectrophotometric assay in comparison with quercetin and orlistat. Alkoxyaurone derivatives with long-chain (6-10 carbon) alkoxy substituents showed greater potency. Of them, 4,6-dialkoxyaurone 8 displayed the highest activity against pancreatic lipase (IC(50) of 1.945 +/- 0.520 microM) relative to quercetin (IC(50) of 86.98 +/- 3.859 microM) and orlistat (IC(50) of 0.0334 +/- 0.0015 microM). Fluorescence quenching measurement confirmed the affinity of alkoxyaurone derivatives to pancreatic lipase. Kinetic study showed 8 inhibited lipase through a competitive mechanism (Ki of 1.288 +/- 0.282 microM). Molecular docking results clarified the role of long-chain substituents on ring A in interacting with the hydrophobic pockets and pushing the inhibitor molecule closer to the catalytic triad. The findings in this study may contribute to the development of better pancreatic lipase inhibitors with aurone structure.