1-(3-fluorophenyl)-3-(furan-3-ylmethyl)thiourea | 431065-78-0

• 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: 1-(3-fluorophenyl)-3-(furan-3-ylmethyl)thiourea
• 英文别名: 1-(3-Fluorophenyl)-3-(furan-2-ylmethyl)thiourea
• CAS: 431065-78-0
• 化学式: C₁₂H₁₁FN₂OS
• 分子量: 250.297
• InChiKey: VAZUOFUISAMTIR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  69.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-(3-fluorophenyl)-3-(furan-3-ylmethyl)thiourea 在 N-甲基吗啉 、 tin(II) chloride dihdyrate 、 copper diacetate 、 sodium acetate 、 manganese triacetate 作用下， 以 乙醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 生成 (Z)-5-(4-((S)-2-(((benzyloxy)carbonyl)amino)propanamido)phenyl)-2-((3-fluorophenyl)imino)-3-(furan-2-ylmethyl)-4-oxothiazolidin-5-yl acetate
  参考文献：
  名称：

  Inhibitors of HCV NS5A: From Iminothiazolidinones to Symmetrical Stilbenes

  摘要：

  The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in a genotype 1b replicon assay via a high-throughput screening campaign. A more potent analogue, BMS-824 (18), was used in resistance mapping studies, which revealed that inhibitory activity was related to disrupting the function of the HCV nonstructural protein 5A. Despite the development of coherent and interpretable SAIL, it was subsequently discovered that in DMSO 18 underwent an oxidation and structural rearrangement to afford the thiohydantoin 47, a compound with reduced HCV inhibitory activity. However, HPLC bioassay fractionation studies performed after incubation of 18 in assay media led to the identification of fractions containing a dimeric species 48 that exhibited potent antiviral activity. Excision of the key elements hypothesized to be responsible for antiviral activity based on SAR observations reduced 48 to a simplified, symmetrical, pharmacophore realized most effectively with the stilbene 55, a compound that demonstrated potent inhibition of HCV in a genotype 1b replicon with an EC50 = 86 pM.

  DOI：

  10.1021/ml1002647
• 作为产物：
  描述：

  2-呋喃甲胺 、 异硫氰酸(3-氟苯)酯 以 乙腈 为溶剂， 反应 5.0h， 以70%的产率得到1-(3-fluorophenyl)-3-(furan-3-ylmethyl)thiourea
  参考文献：
  名称：

  1,3-二取代硫脲的卤素衍生物的合成，结构研究和生物学评价

  摘要：

  背景：卤素取代的硫脲衍生物具有充分证明的抗微生物，抗病毒和抗癌特性。 目的：这项工作评估了新合成的氟化硫脲化合物的抗菌和细胞毒性活性。 方法：通过4-氨基-1-苄基哌啶（1a-14a）或糠胺（1b-14b）与氟化异硫氰酸酯的缩合反应获得两个系列的硫脲。抗HIV-1活性评估是基于MTT方法测定的，在成对生长的MT-4细胞中病毒诱导的细胞致病性的抑制作用。根据CLSI指南，使用Mueller-Hinton II琼脂培养基在标准条件下通过圆盘扩散法检查抗菌效力。使用Mueller-Hinton琼脂和2％葡萄糖和0.5μg/ mL亚甲基蓝染料培养基评估抗真菌作用。HaCaT和A549细胞的生存能力通过线粒体脱氢酶测定MTT盐转化率来评估，而乳酸脱氢酶从胞质溶胶释放到培养基中是细胞死亡的标志。 结果：X射线晶体学研究表明分子2a，7a，2b和7b所采用的构象。化合物1a和14a被证明对MT-4细胞和

  DOI：

  10.2174/1570180814666170106121025

文献信息

• Synthesis, Structural Studies and Biological Evaluation of Halogen Derivatives of 1,3-Disubstituted Thiourea
  作者：Anna Bielenica、Karolina Stepien、Aleksandra Sawczenko、Tadeusz Lis、Anna E. Koziol、Silvia Madeddu、David Collu、Filippo Iuliano、Anita Kosmider、Marta Struga

  DOI：10.2174/1570180814666170106121025

  日期：2017.6.6

  mitochondrial dehydrogenase, whereas release of lactate dehydrogenase from the cytosol to culture medium was a marker of the cell death. Results: The X-ray crystallography studies showed the conformations adopted by the molecules 2a, 7a, 2b and 7b. Compounds 1a and 14a proved cytotoxic against MT-4 cells and different other cell lines derived from human haematological tumors (CC50 < 10 μM). They influenced on

  背景：卤素取代的硫脲衍生物具有充分证明的抗微生物，抗病毒和抗癌特性。 目的：这项工作评估了新合成的氟化硫脲化合物的抗菌和细胞毒性活性。 方法：通过4-氨基-1-苄基哌啶（1a-14a）或糠胺（1b-14b）与氟化异硫氰酸酯的缩合反应获得两个系列的硫脲。抗HIV-1活性评估是基于MTT方法测定的，在成对生长的MT-4细胞中病毒诱导的细胞致病性的抑制作用。根据CLSI指南，使用Mueller-Hinton II琼脂培养基在标准条件下通过圆盘扩散法检查抗菌效力。使用Mueller-Hinton琼脂和2％葡萄糖和0.5μg/ mL亚甲基蓝染料培养基评估抗真菌作用。HaCaT和A549细胞的生存能力通过线粒体脱氢酶测定MTT盐转化率来评估，而乳酸脱氢酶从胞质溶胶释放到培养基中是细胞死亡的标志。 结果：X射线晶体学研究表明分子2a，7a，2b和7b所采用的构象。化合物1a和14a被证明对MT-4细胞和
• Iminothiazolidinones as inhibitors of HCV replication
  申请人：Romine Lee Jeffrey

  公开号：US20050096364A1

  公开（公告）日：2005-05-05

  Compounds having the structure of formula I are described wherein R, R′, R 1 , R 2 , and R 3 are as defined in the specification. The compounds can inhibit hepatitis C virus (HCV) replication, and in particular the function of the HCV NS5A protein.

  本文描述了具有公式I结构的化合物，其中R，R'，R1，R2和R3的定义如规范中所述。这些化合物可以抑制丙型肝炎病毒（HCV）的复制，特别是HCV NS5A蛋白的功能。
• Combination pharmaceutical agents as inhibitors of HCV replication
  申请人：Colonno Richard

  公开号：US20050069522A1

  公开（公告）日：2005-03-31

  Disclosed are combination pharmaceutical agents for the treatment of an HCV infection comprising a compound effective to inhibit the function of the HCV NS5A protein and another compound having anti-HCV activity. Compounds which can inhibit the function of the NS5A protein having the structure of formula I are described wherein R, R′, R 1 , R 2 , and R 3 are as defined in the specification. The other compounds having anti-HCV activity are effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH and a nucleoside analog for the treatment of an HCV infection.

  本发明涉及一种用于治疗HCV感染的联合药物组合，包括一种有效抑制HCV NS5A蛋白功能的化合物和具有抗HCV活性的另一种化合物。其中，可以抑制NS5A蛋白功能的化合物具有式I的结构，其中R、R'、R1、R2和R3的定义如规范中所述。具有抗HCV活性的其他化合物有效地抑制来自以下组的靶点的功能，包括HCV金属蛋白酶、HCV丝氨酸蛋白酶、HCV聚合酶、HCV解旋酶、HCV NS4B蛋白、HCV进入、HCV组装、HCV离子、HCV NS5A蛋白、IMPDH和核苷类似物，用于治疗HCV感染。
• Discovery of Potent Hepatitis C Virus NS5A Inhibitors with Dimeric Structures
  作者：Julie A. Lemm、John E. Leet、Donald R. O'Boyle、Jeffrey L. Romine、Xiaohua Stella Huang、Daniel R. Schroeder、Jeffrey Alberts、Joseph L. Cantone、Jin-Hua Sun、Peter T. Nower、Scott W. Martin、Michael H. Serrano-Wu、Nicholas A. Meanwell、Lawrence B. Snyder、Min Gao

  DOI：10.1128/aac.00146-11

  日期：2011.8

  The exceptionalin vitropotency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into anin vivoeffect in proof-of-concept clinical trials. Although the 50% effective concentration (EC₅₀) of the initial lead, the thiazolidinone BMS-824, was ∼10 nM in the replicon assay, it underwent transformation to other inhibitory species after incubation in cell culture medium. The biological profile of BMS-824, including the EC₅₀, the drug concentration required to reduce cell growth by 50% (CC₅₀), and the resistance profile, however, remained unchanged, triggering an investigation to identify the biologically active species. High-performance liquid chromatography (HPLC) biogram fractionation of a sample of BMS-824 incubated in medium revealed that the most active fractions could readily be separated from the parental compound and retained the biological profile of BMS-824. From mass spectral and nuclear magnetic resonance data, the active species was determined to be a dimer of BMS-824 derived from an intermolecular radical-mediated reaction of the parent compound. Based upon an analysis of the structural elements of the dimer deemed necessary for anti-HCV activity, the stilbene derivative BMS-346 was synthesized. This compound exhibited excellent anti-HCV activity and showed a resistance profile similar to that of BMS-824, with changes in compound sensitivity mapped to the N terminus of NS5A. The N terminus of NS5A has been crystallized as a dimer, complementing the symmetry of BMS-346 and allowing a potential mode of inhibition of NS5A to be discussed. Identification of the stable, active pharmacophore associated with these NS5A inhibitors provided the foundation for the design of more potent inhibitors with broad genotype inhibition. This culminated in the identification of BMS-790052, a compound that preserves the symmetry discovered with BMS-346.

  摘要丙型肝炎病毒（HCV）NS5A抑制剂BMS-790052的超强生命力已在概念验证临床试验中转化为活体效应。虽然最初的先导药物噻唑烷酮 BMS-824 在复制子实验中的 50% 有效浓度（EC50）为 10 nM，但在细胞培养基中培养后，它已转变为其他抑制种类。然而，BMS-824 的生物学特性，包括半数致死浓度（EC50）、使细胞生长减少 50%所需的药物浓度（CC50）和耐药性特性保持不变，这引发了对生物活性物种的鉴定研究。对培养基中培养的 BMS-824 样品进行高效液相色谱（HPLC）生物图谱分馏后发现，最有活性的馏分很容易从母体化合物中分离出来，并保留了 BMS-824 的生物特征。根据质谱和核磁共振数据，活性物种被确定为 BMS-824 的二聚体，来自母体化合物分子间自由基介导的反应。根据对二聚体结构元素的分析，认为该二聚体具有抗 HCV 活性的必要条件，合成了二苯乙烯衍生物 BMS-346。该化合物表现出卓越的抗 HCV 活性，并显示出与 BMS-824 相似的耐药性特征，化合物敏感性的变化映射到 NS5A 的 N 末端。NS5A的N末端已结晶为二聚体，补充了BMS-346的对称性，从而可以讨论NS5A的潜在抑制模式。确定与这些 NS5A 抑制剂相关的稳定、活性药理机制为设计具有广泛基因型抑制作用的更强效抑制剂奠定了基础。最终，BMS-790052 被鉴定出来，这是一种保留了 BMS-346 对称性的化合物。
• US7183302B2
  申请人：——

  公开号：US7183302B2

  公开（公告）日：2007-02-27