Molecular insights into genistein-NSAID hybrids—synthesis, characterisation and DFT study

Genistein (GEN) is one of the pharmaceutically valuable phenolic compounds, which belongs to the isoflavone group of flavonoids and is a natural phytohormone found mainly in soybeans and red clover. It affects estrogen receptors, functioning as a selective estrogen receptor modulator (SERM) with anti-inflammatory and antioxidant activity. The presence of reactive phenolic groups in genistein provides an opportunity to expand its structure by introducing components responsible for anti-inflammatory properties. Such an innovative combination of a compound with anticancer and antioxidant potential with an anti-inflammatory compound (NSAID) may lead to interesting new derivatives with dual mechanisms of biological action. The synthesis and characterisation of genistein-NSAID hybrid compounds (ibuprofen, ketoprofen, naproxen, flurbiprofen) was conducted, together with a comprehensive structural and quantum chemistry DFT (density functional theory) computational analysis allowing the description of ¹ H-NMR and ¹³ C-NMR spectroscopic properties of the starting compounds and the resulting hybrids. The study resulted in the formation of seven hybrid GEN-NSAID derivatives. In the case of ibuprofen, ketoprofen and flurbiprofen, a mixture of isomeric hybrid GEN-4’-NSAID and GEN-7-NSAID derivatives was obtained, whereas, for naproxen, only GEN-4’-NSAID was formed. The structural characteristics of the resulting compounds were determined using MS, IR, ¹ H-NMR and ¹³ C-NMR spectroscopic methods. The most accurate DFT computational methods for predicting ¹ H-NMR and ¹³ C-NMR spectra were also established with statistical parameters to assess their accuracy.