The synthesis of phenyl-γ-hydroxyketones through Heck coupling and subsequent opening of the tetrahydrofuran ring by the nucleophilic attack of a water molecule catalyzed by PdCl₂·Gly₂under microwave irradiation.

The present study describes the synthesis of an analog of the anti‐inflammatory drug fenbufen, a compound which has recently attracted of renewed interest in the treatment of chronic degenerative diseases such as cancer and rheumatoid arthritis. The molecule under consideration, 4‐(4‐methoxyphenyl)‐4‐oxobutanoic acid, is distinguished from fenbufen by the absence of the biphenyl moiety. This characteristic results in the generation of nontoxic metabolites during biotransformation. The incorporation of aromatic amino acid residues (phenylalanine and tyrosine) led to the modulation of the hybrid NSAID–amino acid and NSAID–peptide derivatives, thereby altering their biological activity and safety profile. The inhibitory activity against the dual cyclooxygenase‐2/5‐lipoxygenase system was evaluated using molecular docking, free energy calculations, and per‐residue decomposition analysis based on molecular dynamics simulations. Compounds containing a tyrosine residue or the Tyr‐Phe dipeptide exhibited strong drug–receptor binding affinities and long‐term stability during our simulations, in some cases outperforming the reference drugs celecoxib and zileuton. The values of the free energy (Δ G ) obtained through the Boltzmann equation demonstrated a strong correlation with the energy decomposition data, particularly for the lead compounds, which exhibited stabilizing interactions with the heme prosthetic group and the Fe ²⁺ ion. These findings provide substantial support for the identification of these molecules as promising candidates for further preclinical development.

In this paper, the synthesis of compounds based on a hybrid structure combining a fenbufen analog (a nonsteroidal anti-inflammatory drug, NSAID) with amino acids or peptides is described. Additionally, a detailed molecular docking analysis was performed to investigate their drug–receptor interactions with inflammation-related enzymes COX-2 and 5-LOX. The hybrid compound that demonstrated the best interaction was further evaluated through molecular dynamics simulations, and its binding free energy (ΔG) was calculated using the Molecular Mechanics Poisson–Boltzmann Surface Area (MMPBSA) method.