2-Arylbenzo[<i>b</i>]furan derivatives as potent human lipoxygenase inhibitors

<p>Human lipoxygenases (LOXs) have been emerging as effective therapeutic targets for inflammatory diseases. In this study, we found that four natural 2-arylbenzo[<i>b</i>]furan derivatives isolated from <i>Artocarpus heterophyllus</i> exhibited potent inhibitory activities against human LOXs, including moracin C (<b>1</b>), artoindonesianin B-1 (<b>2</b>), moracin D (<b>3</b>), moracin M (<b>4</b>). In our <i>in vitro</i> experiments, compound <b>1</b> was identified as the most potent LOX inhibitor and the moderate subtype selective inhibitor of 12-LOX. Compounds <b>1</b> and <b>2</b> act as competitive inhibitors of LOXs. Moreover, <b>1</b> significantly inhibits LTB4 production and chemotactic capacity of neutrophils, and is capable of protecting vascular barrier from plasma leakage <i>in vivo</i>. In addition, the preliminary structure–activity relationship analysis was performed based on the above four naturally occurring (<b>1</b>–<b>4</b>) and six additional synthetic 2-arylbenzo[<i>b</i>]furan derivatives. Taken together, these 2-arylbenzo[<i>b</i>]furan derivatives, as LOXs inhibitors, could represent valuable leads for the future development of therapeutic agents for inflammatory diseases.</p>