3-(2-Trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles: Mastering anti-inflammation and analgesia while mitigating gastrointestinal side effects

A series of 3-(2-trifluoromethyl-3-aryl-4H-chromen-4-yl)-1H-indoles (5-1 to 5-29) were developed and characterized. Most of compounds were found to be potent for inhibiting the production of NO in LPS-induced RAW264.7 cells, of which 3-(3-(4-chlorophenyl)-6-methoxy-2-(trifluoromethyl)-4H-chromen-4-yl)-1H-indole (5-25) was the most optimal (IC₅₀ = 4.82 ± 0.34 μΜ) and was capable of significantly suppressing the release of PGE₂. The inhibitory effect of 5-25 on human recombinant COX-2 (IC₅₀ = 51.7 ± 1.3 nM) was measured and molecular docking was performed, determining 5-25 as a COX-2 inhibitor. Additionally, the interaction between 5-25 and COX-2 was determined by the CETSA technique. Then, 5-25 inhibited the degradation of IκB, the phosphorylation and nuclear translocation of NF-κB p65, and the expression of COX-2 and iNOS. Moreover, it was verified that 5-25 exhibited efficacy in rodent models of inflammation and pain, encompassing the paw edema, cotton pellet-induced granuloma, acid-induced writhing, and adjuvant-induced arthritis models. Therefore, the mechanism of 5-25 may be to bind to COX-2 and exert anti-inflammatory and analgesic effects in vitro and in vivo by suppressing the NF-κB pathway. Encouragingly, in comparison with indomethacin, 5-25 exhibited a lower ulcerative potential in rats, as manifested by generating smaller areas and fewer ulcers, less inflammatory infiltration, a lower expression of MMP-9, and less apoptosis. In conclusion, 5-25 is a candidate drug with high activity and low ulcerogenic potential, and it deserves further research for the treatment of inflammation, pain, and other symptoms in which COX-2 plays a role in their pathogenesis.