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.