Synthesis of Novel Pyrimidin-4-One Bearing Piperazine Ring-Based Amides as Glycogen Synthase Kinase-3β Inhibitors with Antidepressant Activity

Abstract

Novel pyrimidin-4-one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase-3β (GSK-3β) inhibitors. Among all the synthesized compounds, compound 5 (3-methyl-6-phenyl-2-(piperazin-1-yl)-3,4-dihydropyrimidin-4-one) exhibited the most potent inhibitory activity against GSK-3β with IC50 value of 74 nm. The molecular docking studies were performed to elucidate the binding modes of the compounds with the target, and a crucial interaction involving hydrogen bond formation with Val-135 to the active site of GSK-3β was observed. Furthermore, the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity, and compound 5 showing highest inhibition of GSK-3β was also found to significantly reduce the duration of immobility at 50 mg/kg, when compared with fluoxetine, a known antidepressant drug. The results of our study suggest that compound 5 may serve as a valuable template for the design and development of inhibitors of GSK-3β with antidepressant activity.