Structure-based design, synthesis, PPAR-γ activation, and molecular docking of N-substituted phthalimides

N-substituted phthalimides showed peroxisome proliferator-activated receptors-gamma activation in rat liver epithelial Ac2F cells in our previous study. In order to explore better peroxisome proliferator-activated receptors-gamma agonists, new N-substituted phthalimide derivatives were designed and synthesized based on a pharmacophore study of natural peroxisome proliferator-activated receptors-gamma agonist paecilocin A and synthetic leads. Peroxisome proliferator-activated receptors-gamma activation by the new derivatives was evaluated using rat liver epithelial Ac2F cells at a concentration of 10 mu M (same as previous study). All the new derivatives showed comparable or better activities than that of rosiglitazone, in which 3-hydroxy-N-(p-methoxy-phenethyl) phthalimide (compound 6) appeared as the best. Molecular docking suggested that the free hydroxyl group on the phthalimide head, a proper hydrophobic tail including a phenyl linker, were beneficial for peroxisome proliferator-activated receptors-gamma activation. These N-substituted phthalimide derivatives are valuable as scaffolds for new peroxisome proliferator-activated receptors-gamma agonists.