| Summary: | A small fenbufen library comprising 18 compounds was prepared via Suzuki Miyara coupling. The five-step preparations deliver 9–17% biphenyl compounds in total yield. These fenbufen analogs exert insignificant activity against the IL-1 release as well as inhibiting cyclooxygenase 2 considerably. Both the <i>para</i>-amino and <i>para</i>-hydroxy mono substituents display the most substantial COX-2 inhibition, particularly the latter one showing a comparable activity as celecoxib. The most COX-2 selective and bioactive disubstituted compound encompasses one electron-withdrawing methyl and one electron-donating fluoro groups in one arene. COX-2 is selective but not COX-2 to bioactive compounds that contain both two electron-withdrawing groups; disubstituted analogs with both resonance-formable electron-donating dihydroxy groups display high COX-2 activity but inferior COX-2 selectivity. In silico simulation and modeling for three COX-2 active—<i>p</i>-fluoro, <i>p</i>-hydroxy and <i>p</i>-amino—fenbufens show a preferable docking to COX-2 than COX-1. The most stabilization by the <i>p</i>-hydroxy fenbufen with COX-2 predicted by theoretical simulation is consistent with its prominent COX-2 inhibition resulting from experiments.
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