benzyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate | 681257-88-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• 英文别名: Benzyl 6-methyl-4-(3-hydroxyphenyl)-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate；benzyl 4-(3-hydroxyphenyl)-6-methyl-2-sulfanylidene-3,4-dihydro-1H-pyrimidine-5-carboxylate
• CAS: 681257-88-5
• 化学式: C₁₉H₁₈N₂O₃S
• 分子量: 354.43
• InChiKey: BHDPFSLFZXFXCO-UHFFFAOYSA-N

物化性质

• 沸点：
  522.1±60.0 °C(Predicted)
• 密度：
  1.36±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  103
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  乙酰丙酮苄酯 、 间羟基苯甲醛 、 硫脲 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 以56%的产率得到benzyl 4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
  参考文献：
  名称：

  Synthesis, Antileishmanial Activity and Molecular Docking Study of New 3,4-Dihydropyrimidinones/Thiones

  摘要：

  由于利什曼属出现了对药物无反应的菌株，而目前的化疗又存在毒副作用，因此有必要寻找新型抗利什曼病药物。本研究合成了新的二氢嘧啶/硫酮-5-羧酸盐/甲酰胺衍生物，并对其进行了抗利什曼原虫的生物评估。一些衍生物表现出了良好的抗利什曼病活性（IC50s 24.7 - 2223.9 μM）。生物学评估结果表明，化合物 4 是最有效的抗利什曼病剂。与 Glucantime（对照药物）相比，化合物 1、3、4、8 和 9 具有显著的活性。对于 5-甲酰胺和 5-羧酸盐系列，研究发现 4-（3-取代苯基）位置的立体阻碍是抗利什曼病作用的决定因素，它在 4-苯基分子的元位置附近形成了一个疏水口袋。分子对接方法将蝶啶还原酶 1 作为有效的利什曼病原体靶标，结果表明 5-羧酸盐衍生物与酶的辅助因子（即烟酰胺腺嘌呤二核苷酸磷酸酯（NDP602））产生了 H 键作用。其相互作用模式与之前报道的药物（如三甲氧苄啶）较为相似。结合效率指数（BEIs）与抗利什曼病的 IC50 值一致。

  DOI：

  10.1007/s11094-021-02536-4

文献信息

• Synthesis, biological evaluation and molecular docking study of dihydropyrimidine derivatives as potential anticancer agents
  作者：Sahand Safari、Reza Ghavimi、Nima Razzaghi‐Asl、Saghi Sepehri

  DOI：10.1002/jhet.3822

  日期：2020.3

  Subsequently, they were screened for in vitro anticancer effect. These analogues revealed good cytotoxic activity against three human cancer cell lines including MCF‐7, HepG‐2, and A549. Among these analogues, compounds 4d and 4h were the most potent against three cell lines. Cell viability assays indicated 4a and 4c had lower cytotoxicity. In vitro cytotoxicity study on all synthesized compounds demonstrated

  通过一锅Biginelli三组分缩合反应制备了一系列二氢嘧啶类似物，并通过NMR，FT-IR，MS光谱和元素分析进行​​了表征。随后，筛选它们的体外抗癌作用。这些类似物显示出对三种人类癌细胞系（包括MCF-7，HepG-2和A549）具有良好的细胞毒活性。在这些类似物中，化合物4d和4h对三种细胞系最有效。细胞活力测定表明4a和4c具有较低的细胞毒性。对所有合成化合物的体外细胞毒性研究表明，在二氢嘧啶苯环的C4位引入吸电子取代基有助于抑制增殖。此外，计算机分子对接的结果表明实验活性与计算的结合亲和力之间具有良好的相关性。事实证明4d和4h是最强的化合物。类似物的结合模式提出了疏水相互作用和具有Eg5活性位点的氢键的参与。结构活性关系研究表明，在二氢嘧啶苯环的C4位上引入吸电子取代基对于该生物活性很重要。
• Novel Dihydropyrimidine Derivatives And Their Use As Anti-Cancer Agents
  申请人：Lopez Roman

  公开号：US20080145453A1

  公开（公告）日：2008-06-19

  The invention concerns molecules of formula (I), drugs containing same and their use as anti-cancer agents.

  本发明涉及公式(I)的分子，含有该分子的药物以及它们作为抗癌剂的使用。
• Monastrol, a 3,4-dihydropyrimidin-2(1 H )-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α 1 β 2 δ GABA A receptors
  作者：Maria Damgaard、Anas Al-Khawaja、Mia Nittegaard-Nielsen、Rebekka F. Petersen、Petrine Wellendorph、Bente Frølund

  DOI：10.1016/j.ejmech.2017.06.024

  日期：2017.9

  The (alpha(4)beta delta subtype of the gamma-aminobutyric acid (GABA) type A receptors (GABA(A)Rs) has been shown to be implicated in high-affinity binding of the neuromodulator gamma-hydroxybutyric acid (GHB), but may not be the only GHB high-affinity binding sites. Monastrol has been identified as a modulator of GHB high affinity binding and is furthermore reported as an allosteric modulator selective for the alpha(1)beta(2)delta GABAARs. Therefore, structural determinants for selectivity at the two targets were investigated. 39 structural diverse monastrol analogues were synthesized by employing the Biginelli cyclocondensation and examined for modulation of GHB high-affinity binding using the GHB-specific ligand [H-3]NCS-382 [(E,RS)=6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid] in rat brain homogenate. Only limited modifications were allowed on the monastrol scaffold in order to maintain modulation of GHB high-affinity binding. However, three analogues of monastrol (11,12 and 24) enhanced the maximal binding of [H-3]NCS-382 to a higher maximal level than seen for monastrol itself. Selected compounds were further characterized as modulators at alpha(1)beta(2)delta, alpha(1)beta(2)gamma(2s) and alpha(1)beta(2) GABA(A)Rs. Most of these modulators were shown to have delta-specific GABA-potentiating effects. The dual effect shown for monastrol to modulate the GHB high-affinity binding and alpha(1)beta(2)delta GABA(A)R activity was also shown for the compounds 11, 18 and 24. Compound 29 displayed minimal modulatory effect on GABA(A)Rs and therefore appears to be a GHB high-affinity binding preferring modulator. However, compounds 34 and 37 were shown to be alpha(1)beta(2)delta GABA(A)R selective modulators, without modulatory effects on GHB high-affinity binding. Thus, our study shows that minor modifications in the structure of monastrol affects the selectivity profile for the two targets under study enabling separation of the dual activity. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Synthesis, Antileishmanial Activity and Molecular Docking Study of New 3,4-Dihydropyrimidinones/Thiones
  作者：Behnam Mohammadi-Ghalehbin、Saghi Sepehri、Negin Nejatkhah、Sahand Safari、Zahra Hosseinali、Sahar Sabour、Nima Razzaghi-Asl

  DOI：10.1007/s11094-021-02536-4

  日期：2022.1

  Appearance of drug-unresponsive strains of Leishmania genus and toxic side effects of current chemotherapies necessitate the search for novel antileishmanial agents. Within present contribution, new dihydropyrimidine/thione-5-carboxylates/carboxamide derivatives were synthesized and biologically assessed against Leishmania major promastigotes. A few derivatives exhibited promising antileishmanial activities (IC50s 24.7 – 2223.9 μM). Results of biological assessment revealed compound 4 as the most potent antileishmanial agent. Compounds 1, 3, 4, 8 and 9 exhibited significant activity with regard to Glucantime (control drug). For both 5-carboxamide and 5-carboxylate series, it was found that steric hindrance of 4-(3-substituted phenyl) position was determinant in antileishmanial effect proposing a hydrophobic pocket near meta position of 4-phenyl moiety. Molecular docking approach vs. pteridine reductase 1 as a validated leishmanial target revealed that 5-carboxylate derivatives made H-bond with enzyme cofactor, i.e., nicotinamide adenine dinucleotide phosphate (NDP602). Interaction pattern was relatively similar to previously reported drugs such as trimethoprim. Binding efficiency indices (BEIs) were in accordance with antileishmanial IC50 values.

  由于利什曼属出现了对药物无反应的菌株，而目前的化疗又存在毒副作用，因此有必要寻找新型抗利什曼病药物。本研究合成了新的二氢嘧啶/硫酮-5-羧酸盐/甲酰胺衍生物，并对其进行了抗利什曼原虫的生物评估。一些衍生物表现出了良好的抗利什曼病活性（IC50s 24.7 - 2223.9 μM）。生物学评估结果表明，化合物 4 是最有效的抗利什曼病剂。与 Glucantime（对照药物）相比，化合物 1、3、4、8 和 9 具有显著的活性。对于 5-甲酰胺和 5-羧酸盐系列，研究发现 4-（3-取代苯基）位置的立体阻碍是抗利什曼病作用的决定因素，它在 4-苯基分子的元位置附近形成了一个疏水口袋。分子对接方法将蝶啶还原酶 1 作为有效的利什曼病原体靶标，结果表明 5-羧酸盐衍生物与酶的辅助因子（即烟酰胺腺嘌呤二核苷酸磷酸酯（NDP602））产生了 H 键作用。其相互作用模式与之前报道的药物（如三甲氧苄啶）较为相似。结合效率指数（BEIs）与抗利什曼病的 IC50 值一致。