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Design, Stereoselective Synthesis, and in Silico Evaluation of Novel Pyran‐Based C ‐Fucosides as Potential COX‐2 Inhibitors

Year: 2026

Type: article

Abstract: C ‐Glycosides represent a class of structurally robust and pharmacologically significant molecules due to their stable anomeric C–C bonds and diverse biological profiles. Herein, a novel series of stereodefined C ‐fucosides, specifically (2 S ,3 S ,6 R )‐2‐methyl‐6‐aryl/aryloxy‐3,6‐dihydro‐2 H ‐pyran‐3‐ols ( 1 – 8 ), was efficiently synthesized from 3,4‐ O ‐carbonate‐L‐fucal via palladium‐catalyzed cross‐coupling with diverse aryltrifluoroborates. The reactions proceeded under mild conditions with excellent stereoselectivity, delivering high yields (78%–94%). All α ‐ C ‐glycosides were thoroughly characterized by nuclear magnetic resonance, high‐resolution mass spectrometry, and optical rotation. To evaluate their therapeutic potential, an integrated in silico assessment was conducted. ADMET profiling using SwissADME, BOILED‐Egg, and ProTox‐II predicted favorable pharmacokinetics and acceptable toxicity, identifying compounds 3 , 6 , and 8 as low‐toxicity candidates (Class 5). Molecular docking against cyclooxygenase‐2 (COX‐2), a validated anti‐inflammatory target, revealed strong binding affinities. Notably, compounds 7 and 2 exhibited docking scores comparable or superior to the reference drug rofecoxib (Vioxx), with MM/GBSA binding energies of −31.99 and −35.26 kcal/mol, respectively. Compound 7 demonstrated a unique binding mode involving hydrogen bonding with TYR355 and π – π stacking with TYR385 and TRP387, whereas compound 2 formed the most distinctive electrostatic interaction among all tested ligands. These results underscore the successful synthesis, structural characterization, and promising computational profile of these pyran‐based C ‐fucosides as potential COX‐2 inhibitors.

Source: European Journal of Organic Chemistry

DOI: 10.1002/ejoc.202501095