Design and synthesis; In silico and in vitro studies of multisubstituted isoxazolidines as selective COX-2 inhibitions and antioxidant activity
Journal of Molecular Structure, cilt.1373, 2026 (SCI-Expanded, Scopus)
- Yayın Türü: Makale / Tam Makale
- Cilt numarası: 1373
- Basım Tarihi: 2026
- Doi Numarası: 10.1016/j.molstruc.2026.146640
- Dergi Adı: Journal of Molecular Structure
- Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Chemical Abstracts Core, Chimica, Compendex, INSPEC, Academic Search Ultimate (EBSCO), Engineering Source (EBSCO)
- Anahtar Kelimeler: Admet profiling, Cyclooxygenase-2, Dynamic simulation, Isoxazolidine, Molecular docking
- Kocaeli Üniversitesi Adresli: Hayır
Özet
The development of selective cyclooxygenase-2 (COX-2) inhibitors represents an effective strategy for designing safer anti-inflammatory agents with reduced gastrointestinal toxicity. This study aims to synthesize and evaluate novel imidazole-based isoxazolidine derivatives as selective COX-2 inhibitors. A novel series of multisubstituted isoxazolidines (3a–h) containing an imidazole moiety was prepared via 1,3-dipolar cycloaddition of achiral nitrones with 1-vinylimidazole under reflux conditions, as well as by microwave irradiation in DMF. The structures of the synthesized compounds were confirmed by FT-IR, ¹H-NMR, and ¹³C-NMR spectral analyses. The evaluation of anti-inflammatory effects was performed by inhibiting protein denaturation and using in vitro assays on the COX-2 enzyme. Among the synthesized derivatives, compound 3c exhibited the most potent inhibitory activity (IC₅₀ = 0.22 ± 0.04 μM), followed by compound 3f (IC₅₀ = 0.32 ± 0.09 μM), which also demonstrated selectivity toward COX-2. Additionally, the compounds showed significant antioxidant activity, with compounds 3e, 3c, and 3f displaying higher activity than ascorbic acid. In silico ADME analysis using SwissADMET indicated favorable pharmacokinetic properties and compliance with Lipinski’s rule of five. Molecular docking studies on COX-2 (PDB ID: 6COX) revealed favorable binding interactions, while molecular dynamics simulations over 200 ns confirmed the stability of compounds 3c and 3f within the active site. These results identify compounds 3c and 3f as promising candidates for selective COX-2 inhibition.