Design, Synthesis, and Anti‐Inflammatory Evaluation In Vitro and In Silico of Novel Flavone Derivatives

Abstract A series of flavone derivatives (4–6) were synthesized via cyclization of 2′ hydroxychalcones 3 into flavonols 4 using the Algar–Flynn–Oyamada reaction. Flavonols 4 were then O ‐cyanomethylated to flavones 5, followed by click coupling to obtain flavone‐tetrazole derivatives 6. The inhibitory ability of synthesized compounds on the production of pro‐inflammatory mediators (nitric oxide and interleukin‐1β) was also investigated. From the obtained results, it appears that only products 3b , 5c , 6a , and 6b at concentrations lower than 56.8 µg/mL have inhibitory ability on the production of NO from lipopolysaccharide‐activated RAW 264.7 cells. In contrast, the other compounds, particularly derivatives 3c , 4b‐c , and 5a‐b , exhibit pro‐inflammatory activity even at low concentrations. For IL‐1α release from THP‐1 cells induced with LPS, flavones bearing the O ‐cyanopropyl group (5a‐c) significantly lowered the production of this pro inflammatory mediator with the concentration lower than 32 µg/mL. The significant interactions of compound 5a‐c with the caspase‐1 protein shown by the molecular docking consolidated the inhibitory activity of these O ‐cyanopropyl flavones. Therefore, these results suggest that compounds 5a‐c can represent a useful starting point for the development of new treatments of the inflammatory disease.