Design, synthesis and biological evaluation of novel diaryl ethers bearing a pyrimidine motif as human Pin1 inhibitors

Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) belongs to peptidyl-prolyl cis-trans isomerase (PPIase) and is a novel promising anticancer target.  Based on the lead structure of benzophenone, a series of novel diarylether derivatives containing a pyrimidine ring were designed and synthesized.  The inhibitory activities on Pin1 of compounds 5a−5d and 6a−6i were evaluated by a protease-coupled enzyme assay.  Of all the evaluated compounds, 6 compounds displayed inhibitory activities.  Molecular docking was performed using FlexX algorithm to explore the binding mode of the active molecules.