Design, microwave-assisted synthesis, and molecular docking of novel schiff base-hybridized urea derivatives with promising anti-inflammatory activities

A new series of Schiff base-hybridized urea derivatives 2–13 was efficiently synthesized via a microwave-assisted green chemistry approach. The reaction involved the condensation of 1-(2-(2-hydrazinyl-2-oxoethoxy)phenyl)-3-propylurea (1) with various substituted isatins or aromatic aldehydes, yielding products in excellent yields (84–90 %) within short reaction times (10–17 min), highlighting the method's efficiency and sustainability. The structures of all synthesized compounds were confirmed using IR, ¹HNMR, ¹³CNMR spectra, and elemental analysis. In vitro COX inhibition assays demonstrated significant selectivity for COX-2 over COX-1. Compound 8 showing the highest selectivity index (SI = 68.66). Moreover, 5, 6, and 7 also exhibited strong COX-2 inhibitory activity (IC₅₀ = 0.78, 0.46, and 0.65 µM, respectively), comparable to that of celecoxib. In vivo evaluation using a carrageenan-induced paw edema model in rats validated their anti-inflammatory efficacy. Compound 8 achieving 49 % edema inhibitions at the 5th hour, outperforming standard drugs. Histopathological analysis supported these findings, revealing reduced inflammation and minimal gastrointestinal toxicity. Molecular docking studies corroborated the experimental results, with strong binding interactions observed at the COX-2 active site. Among the tested derivatives, compound 6 exhibited the most favorable docking score (S = –6.9675 kcal/mol), which correlates with its potent in vitro and in vivo anti-inflammatory activity. This score is comparable to that of celecoxib (–7.4023 kcal/mol), suggesting strong binding affinity.