Virtual screening, synthesis, optimization and anti-inflammatory activity of novel chromones as specific COX-2...

In this study, we pioneered the use of SMARTS screening to construct a chromone database, and the Discovery Studio was used to achieve precise molecular docking of COX-2 through LibDock and CDOCKER, and successfully locked 7 hit compounds from the massive chromone library. In cell experiments, Q7 had a significant inhibitory effect on LPS-induced PGE₂ (IC₅₀ = 68.23 ± 8.94 μM) and NO (IC₅₀ = 44.83 ± 2.01 μM) in RAW264.7 cells, and its anti-inflammatory activity was superior to that of the traditional anti-inflammatory agents ibuprofen [IC₅₀(PGE₂) = 246.5 ± 3.8 μM] and L-canavanine [IC₅₀(NO) = 440.0 ± 7.9 μM]. Still, the activity was not as good as that of celecoxib [IC₅₀ (PGE₂) = 0.882 ± 0.021 μM], and the western blot of Q7 further confirmed its targeted inhibition of COX-2. On this basis, the structure of Q7 was optimized by flexible docking design, and 30 Q7 derivatives were synthesized one by one, all of which showed certain anti-inflammatory activities, among which Q7-9 [IC₅₀(PGE₂) = 0.209 ± 0.022 μM, IC₅₀(COX-2) = 0.121 ± 0.010 μM], Q7-25 [IC₅₀(PGE₂) = 0.267 ± 0.017 μM, IC₅₀(COX-2) = 0.228 ± 0.021 μM] and Q7-26 [IC₅₀(PGE₂) = 0.161 ± 0.018 μM, IC₅₀(COX-2) = 0.137 ± 0.004 μM] exhibited anti-inflammatory activity better than celecoxib and had a moderate selectivity index (SI_Q7-9 > 826). Q7-28 (IC₅₀ = 0.014 ± 0.001 μM) and Q7-29 (IC₅₀ < 0.0128 μM) had significant inhibitory effects on NO. In addition, by constructing a 3D-QSAR model, the anti-inflammatory structures of chromone and isoflavone molecules for COX-2 and iNOS targets were systematically revealed. This study provided an important reference and basis for the research and development of new chromone non-steroidal anti-inflammatory drugs, and Q7-9 was expected to be a candidate drug with high safety and specific COX-2 inhibitors.