Coumarins with Xanthine Oxidase Inhibiting and Radical Scavenging Properties: Tools to Combat Oxidative Stress in Cells

Abstract

 Abstract—Certain representatives from the large natural compound class known as coumarins are known to inhibit the enzyme xanthine oxidase (XO) and are capable of absorbing reactive oxygen species (ROS) produced by XO and other enzymes. These dual properties make coumarins a promising scaffold for the development of agents against reperfusion injuries, which are caused to a large extent by ROS and occur once blood circulation has been restored after ischemic events. A selection of eighteen coumarins was tested for XO inhibition and radical scavenging activities in cell-free assays. The most effective XO inhibitors carried a hydroxyl group in the C7 position of the coumarin scaffold whereas the best radical scavengers were coumarins with two hydroxyl groups in neighboring positions at the phenyl ring. Molecular docking confirmed the essential role of hydroxyl groups for effective enzyme/inhibitor interactions. The coumarins were further investigated in cell-based assays that determined their ability to reduce oxidative stress. As anticipated, the in vivo test results showed that the most effective compounds were those that were both potent XO inhibitors and good radical scavengers, thereby illustrating the potential of coumarins with dual activities for future development.