2,3-Diarylxanthones as Potential Inhibitors of Arachidonic Acid Metabolic Pathways

In response to an inflammatory stimulus, arachidonic acid (AA), the main polyunsaturated fatty acid present in the phospholipid layer of cell membranes, is released and metabolized to a series of eicosanoids. These bioactive lipid mediators of inflammation arise physiologically through the action of the enzymes 5-lipoxygenase (5-LOX) and cyclooxygenases (constitutive COX-1 and inducible COX-2). It is believed that dual inhibition of 5-LOX and COXs may have a higher beneficial impact in the treatment of inflammatory disorders rather than the inhibition of each enzyme. With this demand for new dual-acting anti-inflammatory agents, a range of 2,3-diarylxanthones were tested through their ability to interact in the AA metabolism. In vitro anti-inflammatory activity was evaluated through the inhibition of 5-LOX-catalyzed leukotriene B₄ (LTB₄) formation in human neutrophils and inhibition of COX-1- and COX-2-catalyzed prostaglandin E₂ (PGE₂) formation in human whole blood. The results showed that some of the studied arylxanthones were able to prevent LTB₄ production in human neutrophils, in a concentration-dependent manner. The xanthone with a 2-catechol was the most active one (IC₅₀ ∼ 9 μM). The more effective arylxanthones in preventing COX-1-catalyzed PGE₂ production presented IC₅₀ values from 1 to 7 μM, exhibiting a structural feature with at least one non-substituted aryl group. All the studied arylxanthones were ineffective to prevent the formation of PGE₂ catalyzed by COX-2, up to the maximum concentration of 100 μM. The ability of the tested 2,3-diarylxanthones to interact with both 5-LOX and COX-1 pathways constitutes an important step in the research of novel dual-acting anti-inflammatory drugs.