N-Aryl iminochromenes inhibit cyclooxygenase enzymes via π–π stacking interactions and present a novel class of anti-inflammatory drugs

Abstract

Cyclooxygenase enzymes (COX1/2) have been widely studied and noted for their role in the biosynthesis of inflammation-induced proteins, prostaglandins and thromboxane. Multiple anti-inflammatory drugs have been developed to target these two enzymes, but most of them appeared to have notable adverse effects, especially on the cardiovascular system and lower gastrointestinal tract, suggesting an urgent need for new potent anti-inflammatory drugs. In this study, we screened twenty-two previously synthesized N-aryl iminochromenes (NAIs) for their anti-inflammatory activity by performing COX-1/2 inhibitory assays. Five compounds (1, 10, 14, 15, and 20) that gave the best in vitro anti-inflammatory results were subjected to an in vivo anti-inflammatory assay using the formalin-induced hind rat paw oedema method, followed by in silico studies using indomethacin and celecoxib as standard drugs. Among them, compound 10 stood out as the best candidate, and the percentage reduction in paw oedema at the dose of 20 mg kg⁻¹ body weight was found to be substantially higher with compound 10 than that with indomethacin. This is mostly due to the excellent suitability of the chromene-phenyl scaffold with a highly concentrated area of aromatic residues, which produced good π–π stacking interactions. Taken together, this study strongly suggests compound 10 as a potential candidate for anti-inflammatory drug research.