New Profen-Derived Methoxyaryl Ketones: Synthesis and Structural Characterization

This study reports the design and synthesis of novel profen-derived hybrid compounds incorporating methoxyaryl fragments. The approach combines the well-established anti-inflammatory pharmacophores of profen-class NSAIDs with the structural and pharmacological versatility of methoxylated aromatic systems. The target ketone-based hybrids were efficiently synthesized through Friedel–Crafts acylation using polyphosphoric acid (PPA) as an efficient, reusable, and solvent-minimized acidic medium, enabling regioselective coupling under mild reaction conditions. Systematic optimization of the reaction parameters resulted in high conversion while minimizing the formation of undesired by-products.

A total of ten novel hybrid compounds were synthesized. Five compounds were obtained by acylation of ibuprofen, ketoprofen, naproxen, flurbiprofen, and carprofen with anisole, while five structurally related derivatives were prepared using veratrole as the methoxyaryl coupling partner. The structures of all newly synthesized compounds were confirmed by comprehensive spectroscopic and analytical characterization, including proton and carbon 13 NMR spectroscopies, infrared (IR) spectroscopy, and high-resolution mass spectrometry (HRMS).

The incorporation of electron-donating methoxyaryl groups into profen-derived scaffolds provides additional structural diversity and may facilitate favorable interactions within biological binding sites. The resulting hybrid ketones represent promising molecular frameworks for further pharmacological investigation. Overall, this study demonstrates the potential of a sustainable, solvent-minimized Friedel–Crafts acylation strategy for the development of structurally diverse profen-based hybrids and provides new scaffolds for future studies addressing inflammatory and other pharmacologically relevant targets.