title: Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3β inhibitors with anti-depressant activity.
abstract: 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.
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
authors.forename: Imran
authors.initials: I
authors.lastname: Khan
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (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, Jamia Hamdard (Hamdard University), New Delhi 110 062, India. Electronic address: hhamid@jamiahamdard.ac.in.
authors.forename: Hinna
authors.initials: H
authors.lastname: Hamid
authors.affiliation: Department of Chemistry, Faculty of Science, Jamia Hamdard (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, Jamia Hamdard (Hamdard University), New Delhi 110 062, India.
authors.forename: Abul
authors.initials: A
authors.lastname: Kalam
authors.affiliation: Department of Chemistry, University of Delhi, New Delhi 110 007, India.
authors.forename: Firasat
authors.initials: F
authors.lastname: Hussain
authors.affiliation: CSIR Unit for Research and Development of Information Products, Pune 411038, India.
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Dhulap
mesh_terms: D000928:Antidepressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D000071679:Glycogen Synthase Kinase 3 beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014230:Triazoles; C000620876:pyrimidin-4-one-1,2,3-triazole; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta
keywords: 1,2,3-Triazole; Click chemistry; Glycogen synthase kinase; Molecular docking; Pyrimidin-4-one