title: Synthesis and evaluation of a new series of 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amines and their cyclized products 'pyrimidinylthio pyrimidotriazolothiadiazines' as 15- lipo-oxygenase inhibitors.
abstract: A series of new 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amines and their cyclized products 'pyrimidinylthio pyrimidotriazolothiadiazines' were designed, synthesized, and evaluated as potential inhibitors of 15-lipo-oxygenase (15-LO). Their syntheses started by initial condensation of 2:1 equivalents of pyrimidine with triazole and subsequent nucleophilic displacement of the chlorine atoms with secondary amines and finally cyclocondensation in the presence of NaNH2. The compounds 4d and 4f showed the best IC50 of 15-LO inhibition (IC50 = 9 and 12 μm, respectively). Compounds 4a-g were docked into 15-LO. We suggest that the hydrogen bonds in quaternary nitrogen of piperazine ring of compounds 4d and 4f appear to play major role in lipo-oxygenase inhibition by this set of synthesized analogs and hydrophobic nature of this protein's binding site should be considered in ongoing investigations.
authors.affiliation: Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436, Mashhad, Iran.
authors.forename: Tayebe
authors.initials: T
authors.lastname: Asghari
authors.forename: Mehdi
authors.initials: M
authors.lastname: Bakavoli
authors.forename: Mohammad
authors.initials: M
authors.lastname: Rahimizadeh
authors.forename: Hossein
authors.initials: H
authors.lastname: Eshghi
authors.forename: Sattar
authors.initials: S
authors.lastname: Saberi
authors.forename: Azam
authors.initials: A
authors.lastname: Karimian
authors.forename: Farzin
authors.initials: F
authors.lastname: Hadizadeh
authors.forename: Moreteza
authors.initials: M
authors.lastname: Ghandadi
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001093:Arachidonate 15-Lipoxygenase / Q000378:metabolism*; D054879:Halogenation; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008745:Methylation; D062105:Molecular Docking Simulation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013025:Glycine max / Q000201:enzymology; D013329:Structure-Activity Relationship; D013829:Thiadiazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000588:Amines; D016859:Lipoxygenase Inhibitors; D011743:Pyrimidines; D013829:Thiadiazines; D014230:Triazoles; C012180:2-aminopyrimidine; C045575:1,2,4-triazole; D001093:Arachidonate 15-Lipoxygenase
keywords: 15-LO; 3,5-bis((5-bromo-6-methyl-2-t-aminopyrimidin-4-yl)thio)-4H-1,2,4-triazol-4-amine; docking; heterocyclization; inhibitors; pyrimidinylthio; synthesis