Synthesis and Chiral Separations of Ibuprofen Derivatives for Increased Anti‐Inflammatory Activities

Drug development by derivatization is one of the most important research areas. Fifteen derivatives of ibuprofen were synthesized to overcome the side effects of this medicine. The derivatives were characterized by FT-IR, NMR, and mass spectroscopy. These derivatives are racemic mixtures, and the chiral separation was achieved on Lux Cellulose-1 (250 × 4.6 mm, 5 μm) using various mobile phases of methanol-water and acetonitrile-water. All the racemates have been resolved successfully with the best separations of 2, 11, and 15 derivatives with maximum resolution factors of 8.94 and 13.72 with mobile phases methanol-water (90:10, v/v) and acetonitrile-water (80:20, v/v). The chiral recognition was determined by a modeling approach, confirming that the R-enantiomer elution first, followed by the S-enantiomer. The biological evaluation of these derivatives was carried out by modeling of R- and S-enantiomers with COX-II enzyme. It was determined that all the derivatives had greater binding affinities with COX-II in comparison to ibuprofen, confirming better efficacy of these derivatives. Besides, the maximum binding affinities of 2, 11, and 15 derivatives were -6.4 and -7.0; -7.2 and 7.5; and -7.8 and 8.4 kcal/mol for R- and S-enantiomers, respectively. This clearly indicates that S-enantiomers of these derivatives will be better medications in the future.