Trihydroxyflavones with antioxidant and anti-inflammatory efficacy

The classical anti-inflammatory therapies are frequently ineffective and present numerous and severe side effects, especially in long term use, which requires the development of anti-inflammatory drugs with different scaffolds and mechanisms of action. Owing to the high antioxidant potential and anti-inflammatory activities already inferred for hydroxyflavones, we found it would be relevant to evaluate the anti-inflammatory potential of a series of trihydroxyflavones by testing their ability to scavenge reactive oxygen species (ROS) and reactive nitrogen species (RNS) in cells and cell-free systems and to inhibit the proinflammatory pathways mediated by the enzymes cyclooxygenase (COX) and 5-lipoxygenase (5-LOX), in which reactive species have a proven involvement. The tested trihydroxyflavones proved to be effective inhibitors of neutrophils' oxidative burst and were shown to scavenge different ROS and RNS in cell-free systems. The most active compound in the majority of the assays was 3,3',4'-trihydroxyflavone, which was somehow expected due to the presence of the ortho-dihydroxy in the B-ring, an important structural feature in terms of free radical scavenging activity. Additionally, the studied compounds were able to inhibit the production of leukotriene B(4) by 5-LOX in activated neutrophils. 3,5,7-Trihydroxyflavone was able to inhibit both COX-1 and COX-2, which makes it a dual inhibitor of COX and 5-LOX pathways and, therefore, a promising candidate for a new therapeutic option in the treatment of inflammatory processes.