Abstract
[Display omitted]
•Synthesis of a series of novel Pyrimidin-4-one-1,2,3-triazole conjugates.•In vitro GSK-3β inhibitory and in vivo antidepressant potency evaluation.•Compounds 3n, 3j, 3g, and 3r displayed significant inhibition of GSK-3β.•Compounds 3n, 3j, 3g and 3r also significantly reduced the immobility time.•Compound 3n showed highest GSK-3β inhibition and anti-depressant activity.
GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3β inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin-4(3H)-one) exhibited the most potent inhibitory activity against GSK-3β with IC50 value of 82nM and was also found to exhibit significant antidepressant activity at 50mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3β target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3β were observed.