Asghari Tayebe, Bakavoli Mehdi, Rahimizadeh Mohammad, Eshghi Hossein, Saberi Sattar, Karimian Azam, Hadizadeh Farzin, Ghandadi Moreteza
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436, Mashhad, Iran.
Chem Biol Drug Des. 2015 Feb;85(2):216-24. doi: 10.1111/cbdd.12375. Epub 2014 Jul 10.
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.
设计、合成了一系列新型的3,5-双（（5-溴-6-甲基-2-叔氨基嘧啶-4-基）硫基）-4H-1,2,4-三唑-4-胺及其环化产物“嘧啶硫基嘧啶并三唑并噻二嗪”，并将其作为15-脂氧合酶（15-LO）的潜在抑制剂进行了评估。它们的合成首先是2:1当量的嘧啶与三唑进行缩合，随后用仲胺对氯原子进行亲核取代，最后在氨基钠存在下进行环缩合。化合物4d和4f对15-LO抑制表现出最佳的IC50（分别为IC50 = 9和12μm）。将化合物4a-g对接至15-LO。我们认为，化合物4d和4f哌嗪环季氮中的氢键似乎在这组合成类似物抑制脂氧合酶中起主要作用，并且在后续研究中应考虑该蛋白质结合位点的疏水性。
