Design and synthesis of isoxazolidine core-based selective COX-2 inhibitors: in vitro inhibitor activity and in silico modeling

A novel series of tricyclic isoxazolidine-imidazole derivatives (3a-l) bearing diverse substituted phenyl groups were rationally designed, synthesized, and evaluated as selective cyclooxygenase-2 (COX-2) inhibitors. The target compounds were efficiently obtained via regio- and diastereoselective 1,3-dipolar cycloaddition of C-aryl-3-methylphenyl nitrones with 1-vinylimidazole. Comprehensive spectroscopic characterization was performed using FTIR, ¹H NMR, ¹³C NMR, and LC-MS spectrometry. In vitro assays demonstrated potent COX-2 inhibition with minimal COX-1 activity, achieving high selectivity. Compound 3a exhibited very potent COX-2 inhibition (pIC₅₀ = 6.74 ± 0.05) but weak COX-1 inhibition (pIC₅₀ = 4.19 ± 0.02), the highest selectivity index (SI = 361.1) in the series compared with the reference drug celecoxib (SI = 74.9), compounds 3e and 3j also exhibited higher selectivity than celecoxib. Molecular docking studies elucidated key binding interactions within the COX-2 active site, confirming favorable steric and electronic complementarity. In silico ADMET predictions also revealed the ideal drug-likeness, oral bioavailability, and pharmacokinetic characteristics. The combined synthetic, biological, and computational findings identify these derivatives as promising lead compounds for the development of selective COX-2 inhibitors with possible therapeutic value in the treatment of inflammatory diseases. Density functional theory (DFT) calculations were conducted to investigate the electronic structure and reactivity of compounds 3a, 3e, and 3j. The results indicated that compound 3a was the most reactive and electrophilic derivative. The study also revealed that molecular size and substituent distribution significantly influenced the stability, reactivity, and electronic properties of the investigated compounds.