N-(4-methyl-2-thiazolyl)-3-oxobutanamide | 7145-38-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: N-(4-methyl-2-thiazolyl)-3-oxobutanamide
• 英文别名: N-(4-methyl-thiazol-2-yl)-acetoacetamide；N-(4-Methyl-thiazol-2-yl)-acetoacetamid；2-Acetoacetamido-4-methylthiazole, AldrichCPR；N-(4-methyl-1,3-thiazol-2-yl)-3-oxobutanamide
• CAS: 7145-38-2
• 化学式: C₈H₁₀N₂O₂S
• 分子量: 198.246
• InChiKey: YTHNCQICYKCLCC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  13
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  87.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(4-methyl-2-thiazolyl)-3-oxobutanamide 、 对硝基苯甲醛 在 iron oxide 、 ammonium acetate 作用下， 以 乙醇 为溶剂， 反应 7.0h， 以73%的产率得到2,6-dimethyl-3,5-bis-N-(4-methyl-2-thiazolyl)carbamoyl-4-(4-nitrophenyl)-1,4-dihydropyridine
  参考文献：
  名称：

  Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors

  摘要：

  Alzheimer disease (AD) is a neuronal dementia for which no treatment has been consolidated yet. Major pathologic hallmark of AD is the aggregated extracellular amyloid-beta plaques in the brains of disease sufferers. A beta-peptide is a major component of amyloid plaques and is produced from amyloid precursor protein (APP) via the proteolysis action. An aspartyl protease known as beta-site amyloid precursor protein cleaving enzyme (BACE-1) is responsible for this proteolytic action. Distinctive role of BACE-1 in AD pathogenesis has made it a validated target to develop anti-Alzheimer agents. Our structure-based virtual screening method led to the synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine BACE-1 inhibitors (6a-6p; in vitro hits). Molecular docking and DFT-based ab initio studies using B3LYP functional in association with triple-zeta basis set (TZV) proposed binding mode and binding energies of ligands in the active site of the receptor. In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer (FRET) assay. Most of the synthesized dihydropyridine scaffolds were active against BACE-1 while 6d, 6k, 6n and 6a were found to be the most potent molecules with IC50 values of 4.21, 4.27, 4.66 and 6.78 mu M, respectively. Superior BACE-1 inhibitory activities were observed for dihydropyridine derivatives containing fused/nonfused thiazole containing groups, possibly attributing to the additional interactions with S2-S3 subpocket residues. Relatively reliable correlation between calculated binding energies and experimental BACE-1 inhibitory activities was achieved (R-2 = 0.51). Moreover, compounds 6d, 6k, 6n and 6a exhibited relatively no calcium channel blocking activity with regard to nifedipine suggesting them as appropriate candidates for further modification(s) to BACE-1 inhibitory scaffolds. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.033
• 作为产物：
  描述：

  2-氨基-4-甲基噻唑 、 乙酰乙酸乙酯 生成 N-(4-methyl-2-thiazolyl)-3-oxobutanamide
  参考文献：
  名称：

  Ohta, Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1951, vol. 71, p. 1428

  摘要：

  DOI：

文献信息

• DE607617
  申请人：——

  公开号：——

  公开（公告）日：——
• 2-acylacetylaminothiazole compounds
  申请人：GEN ANILINE WORKS INC

  公开号：US02093214A1

  公开（公告）日：1937-09-14
• Ohta; Tanaka, Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1954, vol. 74, p. 966
  作者：Ohta、Tanaka

  DOI：——

  日期：——
• Ohta, Yakugaku Zasshi/Journal of the Pharmaceutical Society of Japan, 1951, vol. 71, p. 1428
  作者：Ohta

  DOI：——

  日期：——
• Design and synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridines as small molecule BACE-1 inhibitors
  作者：Nima Razzaghi-Asl、Omidreza Firuzi、Bahram Hemmateenejad、Katayoun Javidnia、Najmeh Edraki、Ramin Miri

  DOI：10.1016/j.bmc.2013.09.033

  日期：2013.11

  Alzheimer disease (AD) is a neuronal dementia for which no treatment has been consolidated yet. Major pathologic hallmark of AD is the aggregated extracellular amyloid-beta plaques in the brains of disease sufferers. A beta-peptide is a major component of amyloid plaques and is produced from amyloid precursor protein (APP) via the proteolysis action. An aspartyl protease known as beta-site amyloid precursor protein cleaving enzyme (BACE-1) is responsible for this proteolytic action. Distinctive role of BACE-1 in AD pathogenesis has made it a validated target to develop anti-Alzheimer agents. Our structure-based virtual screening method led to the synthesis of novel 3,5-bis-N-(aryl/heteroaryl) carbamoyl-4-aryl-1,4-dihydropyridine BACE-1 inhibitors (6a-6p; in vitro hits). Molecular docking and DFT-based ab initio studies using B3LYP functional in association with triple-zeta basis set (TZV) proposed binding mode and binding energies of ligands in the active site of the receptor. In vitro BACE-1 inhibitory activities were determined by enzymatic fluorescence resonance energy transfer (FRET) assay. Most of the synthesized dihydropyridine scaffolds were active against BACE-1 while 6d, 6k, 6n and 6a were found to be the most potent molecules with IC50 values of 4.21, 4.27, 4.66 and 6.78 mu M, respectively. Superior BACE-1 inhibitory activities were observed for dihydropyridine derivatives containing fused/nonfused thiazole containing groups, possibly attributing to the additional interactions with S2-S3 subpocket residues. Relatively reliable correlation between calculated binding energies and experimental BACE-1 inhibitory activities was achieved (R-2 = 0.51). Moreover, compounds 6d, 6k, 6n and 6a exhibited relatively no calcium channel blocking activity with regard to nifedipine suggesting them as appropriate candidates for further modification(s) to BACE-1 inhibitory scaffolds. (C) 2013 Elsevier Ltd. All rights reserved.