Benzo[e]isoindole-1,3-diones as Potential Inhibitors of Glycogen Synthase Kinase-3 (GSK-3). Synthesis, Kinase Inhibitory Activity, Zebrafish Phenotype, and Modeling of Binding Mode

Benzo[e]isoindole-1,3-dione derivatives were synthesized, and the effects on GSK-3β activity and zebrafish embryo growth were evaluated. A series of derivatives show obvious inhibitory activity against GSK-3β. The most potent inhibitor, 7,8-dimethoxy-5-methylbenzo[e]isoindole-1,3-dione (8a), shows nanomolar IC50 and obvious phenotype on zebrafish embryo growth associated with the inhibition of GSK-3β at low micromolar concentration. The interaction mode between 8a and GSK-3β was characterized by computational modeling.