Synthesis of novel flufenamic acid hydrazones as predicted COX-2 inhibitors by molecular modelling

Flufenamic acid (FFA), N-(α,α,α-trifluoro-m-tolyl) anthranilic acid, is a derivative of N-phenyl anthranilic acid (fenamates). Flufenamic acid is a non-steroidal anti-inflammatory drug used as a potent analgesic and anti-inflammatory agent in the treatment of osteoarthritis, rheumatoid arthritis, and other painful musculoskeletal illnesses. In the present study, a novel series of hydrazone derivatives of flufenamic acid (2-7) were obtained by reacting different substituted aldehydes with flufenamic acid hydrazide. We prepared 2-[3-(trifluoromethyl) anilino] benzohydrazide (1) by esterifying flufenamic acid (I), followed by treatment with hydrazine hydrate (99%) in absolute ethanol. The structures of all synthesized compounds were confirmed by 1H-NMR, 13C-NMR, and LC/MS. Molecular docking against COX-1 (PDB ID: 3N8Y) and COX-2 (PDB ID: 5IKR) predicted that compounds 3 and 7 had the most favorable COX-2 binding energies in the series (-10.15 kcal mol-1). These computational results indicate preferential binding within the applied docking model; however, they do not demonstrate biological potency or isoform selectivity. Compounds 3 and 7 are therefore proposed as candidates for subsequent enzymatic and cellular validation. KEY WORDS: Flufenamic acid, Hydrazides, Hydrazones, COX-1/COX-2 Bull. Chem. Soc. Ethiop. 2027, 41(1), 15-27. DOI: https://dx.doi.org/10.4314/bcse.v41i1.2