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- Title
Synthesis of Novel Pyrimidin-4-One Bearing Piperazine Ring-Based Amides as Glycogen Synthase Kinase-3 β Inhibitors with Antidepressant Activity.
- Authors
Khan, Imran; Tantray, Mushtaq A.; Hamid, Hinna; Alam, Mohammad Sarwar; Kalam, Abul; Shaikh, Faraz; Shah, Anamik; Hussain, Firasat
- Abstract
Novel pyrimidin-4-one derivatives have been synthesized using EDC coupling and evaluated as glycogen synthase kinase-3 β ( GSK-3 β) 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-3 β with IC50 value of 74 n m. 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-3 β was observed. Furthermore, the synthesized compounds were subjected to in vivo evaluation of their antidepressant activity, and compound 5 showing highest inhibition of GSK-3 β 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-3 β with antidepressant activity.
- Subjects
CHEMICAL synthesis; PIPERAZINE; AMIDES; GLYCOGEN synthase kinase-3; ANTIDEPRESSANTS; FLUOXETINE
- Publication
Chemical Biology & Drug Design, 2016, Vol 87, Issue 5, p764
- ISSN
1747-0277
- Publication type
Article
- DOI
10.1111/cbdd.12710