title: 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.
authors.affiliation: Department of Chemistry, Faculty of Science, Hamdard University, New Delhi, 110 062, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Department of Chemistry, Faculty of Science, Hamdard University, New Delhi, 110 062, India.
authors.forename: Mushtaq A
authors.initials: MA
authors.lastname: Tantray
authors.affiliation: Department of Chemistry, Faculty of Science, Hamdard University, New Delhi, 110 062, India.
authors.forename: Hinna
authors.initials: H
authors.lastname: Hamid
authors.affiliation: Department of Chemistry, Faculty of Science, Hamdard University, New Delhi, 110 062, India.
authors.forename: Mohammad Sarwar
authors.initials: MS
authors.lastname: Alam
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Hamdard University, New Delhi, 110 062, India.
authors.forename: Abul
authors.initials: A
authors.lastname: Kalam
authors.affiliation: National Facility for Drug Discovery, Department of Chemistry, Saurashtra University, Gujarat, 360005, India.
authors.forename: Faraz
authors.initials: F
authors.lastname: Shaikh
authors.affiliation: National Facility for Drug Discovery, Department of Chemistry, Saurashtra University, Gujarat, 360005, India.
authors.forename: Anamik
authors.initials: A
authors.lastname: Shah
authors.affiliation: Department of Chemistry, Faculty of Science, University of Delhi, New Delhi, 110 062, India.
authors.forename: Firasat
authors.initials: F
authors.lastname: Hussain
mesh_terms: D000577:Amides / Q000737:chemistry*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D011744:Pyrimidinones / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D000577:Amides; D000928:Antidepressive Agents; D010879:Piperazines; D011744:Pyrimidinones; D000071679:Glycogen Synthase Kinase 3 beta
keywords: EDC; Pyrimidin-4-one; antidepressant activity; glycogen synthase kinase-3β; molecular docking; piperazine