2-Trifluoromethyl-2H-chromene ethers: The dual triumph of anti-inflammation and analgesia with minimal ulcer threat.

Abstract

In this report, we disclose the design and synthesis of a series of 2-trifluoromethyl-2H- chromene ethers as novel COX-2 inhibitors with low ulcerogenicity. Among them, 6-fluoro-3-(4-methoxyphenyl)-2-(2-(thiophen-3-yl)ethoxy)-2-(trifluoromethyl)-2H-chromene (E25) significantly suppressed LPS-induced release of NO and PGE₂, expression of COX-2 and iNOS, and activation of NF-κB pathway. The inhibitory effect of E25 on human recombinant COX-2 (IC₅₀ = 70.7 ± 4.7 nM) and molecular docking studies suggest that E25 functions as a COX-2 inhibitor. Moreover, the results of the cellular thermal shift assay also substantiate the interaction between E25 and COX-2. E25 manifests potent anti-inflammatory and analgesic efficacy on a par with or even superior to indomethacin in rodent models including carrageenan-induced paw edema, cotton pellet-induced granuloma, acetic acid-induced writhes, and adjuvant-induced arthritis. The possible mechanism of action of E25 might be to bind to COX-2 and suppress the NF-κB pathway as well as the expression of related proteins, thereby exerting anti-inflammatory and analgesic effects. Encouragingly, compared with indomethacin, E25 induces smaller areas and fewer ulcers, a lower level of inflammatory infiltration, a lower expression of MMP-9 and apoptosis of mucosal epithelial cells in rat gastric tissues. Overall, E25 and other analogues are promising candidates worthy of further investigation for the treatment of inflammation and pain, as well as other symptoms in which COX-2 and PGE₂ play a role in their etiology.