6-benzyl-1-((4-fluorobenzyloxy)methyl)-3-hydroxy-5-isopropylpyrimidine-2,4(1H,3H)-dione | 1254831-82-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 6-benzyl-1-((4-fluorobenzyloxy)methyl)-3-hydroxy-5-isopropylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 6-Benzyl-1-[(4-fluorophenyl)methoxymethyl]-3-hydroxy-5-isopropyl-pyrimidine-2,4-dione；6-benzyl-1-[(4-fluorophenyl)methoxymethyl]-3-hydroxy-5-propan-2-ylpyrimidine-2,4-dione
• CAS: 1254831-82-7
• 化学式: C₂₂H₂₃FN₂O₄
• 分子量: 398.434
• InChiKey: IPRNYYLOHLEESV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  70.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-benzyl-1-((4-fluorobenzyloxy)methyl)-3-hydroxy-5-isopropylpyrimidine-2,4(1H,3H)-dione 、 碘甲烷 在 caesium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 3.0h， 以53%的产率得到6-benzyl-1-(((4-fluorobenzyl)oxy)methyl)-5-isopropyl-3-methoxypyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  6-联苯甲基-3-羟基嘧啶-2,4-二酮有效和选择性抑制HIV逆转录酶相关的RNase H

  摘要：

  人类免疫缺陷病毒（HIV）逆转录酶（RT）相关的核糖核酸酶H（RNase H）仍然是未经验证的药物靶标。据报道，HIV RNase H抑制剂通常缺乏显着的抗病毒活性。我们在此报告了3-羟基嘧啶-2,4-二酮（HPD）化学型的新的6-联苯甲基亚型的设计，合成，生化和抗病毒评估。在生化分析中，这种新亚型的类似物可在低纳摩尔范围内有效抑制RT RNase H，而在测试的最高浓度下却不会抑制RT聚合酶（pol）或整合酶链转移（INST）。在基于细胞的测定中，一些类似物在低微摩尔范围内抑制HIV，浓度高达100μM，却没有细胞毒性。

  DOI：

  10.1016/j.ejmech.2018.07.035
• 作为产物：
  描述：

  1-(chloromethoxymethyl)-4-fluorobenzene 在 N,O-双三甲硅基乙酰胺 、 四丁基碘化铵 、 sodium hydride 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 6-benzyl-1-((4-fluorobenzyloxy)methyl)-3-hydroxy-5-isopropylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase

  摘要：

  Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (IN Is). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.

  DOI：

  10.1021/jm1014378

文献信息

• N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase
  作者：Jing Tang、Kasthuraiah Maddali、Christine D. Dreis、Yuk Y. Sham、Robert Vince、Yves Pommier、Zhengqiang Wang

  DOI：10.1021/ml1002162

  日期：2011.1.13

  A new molecular scaffold featuring an N-hydroxyimide functionality and capable of inhibiting both reverse transcriptase (RT) and integrase (IN) of human immunodeficiency virus (HIV) was rationally designed based on 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) non-nucleoside RT inhibitors (NNRTIs). The design involves a minimal 3-N hydroxylation of the pyrimidine ring of HEPT compound to yield a chelating triad which, along with the existing benzyl group, appeared to satisfy major structural requirements for IN binding. In the mean time, this chemical modification did not severely compromise the compound's ability to inhibit RT. A preliminary structure-activity relationship (SAR) study reveals that this N-3 OH is essential for IN inhibition and that the benzyl group on N-1 side chain is more important for IN binding than the one on C-6.
• [EN] N-HYDROXYPYRIMIDINE-2,4-DIONES AS INHIBITORS OF HIV AND HCV<br/>[FR] N-HYDROXYPYRIMIDINE-2,4-DIONES EN TANT QU'INHIBITEURS DU VIH ET VHC
  申请人：UNIV MINNESOTA

  公开号：WO2012047993A2

  公开（公告）日：2012-04-12

  The invention provides antiviral compounds that can be used in therapy against human immunodeficiency virus (HIV) and hepatitis C virus (HCV). Compounds of the invention can be dual targeted inhibitors of HIV, inhibiting both the reverse transcriptase and the integrase enzyme systems, thus increasing the barrier to development of viral resistance in patients. Prodrugs of the inventive antiviral compounds are also provided. Compounds of the invention can be used to treat HCV secondary infections in HIV-afflicted patients, reducing the need for administration of drug cocktails containing multiple, potentially conflicting, medicinal compounds. Methods of synthesis of the compounds and methods of treatment using the compounds are also provided.
• 6-Biphenylmethyl-3-hydroxypyrimidine-2,4-diones potently and selectively inhibited HIV reverse transcriptase-associated RNase H
  作者：Lei Wang、Jing Tang、Andrew D. Huber、Mary C. Casey、Karen A. Kirby、Daniel J. Wilson、Jayakanth Kankanala、Michael A. Parniak、Stefan G. Sarafianos、Zhengqiang Wang

  DOI：10.1016/j.ejmech.2018.07.035

  日期：2018.8

  Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains an unvalidated drug target. Reported HIV RNase H inhibitors generally lack significant antiviral activity. We report herein the design, synthesis, biochemical and antiviral evaluations of a new 6-biphenylmethyl subtype of the 3-hydroxypyrimidine-2,4-dione (HPD) chemotype. In biochemical assays

  人类免疫缺陷病毒（HIV）逆转录酶（RT）相关的核糖核酸酶H（RNase H）仍然是未经验证的药物靶标。据报道，HIV RNase H抑制剂通常缺乏显着的抗病毒活性。我们在此报告了3-羟基嘧啶-2,4-二酮（HPD）化学型的新的6-联苯甲基亚型的设计，合成，生化和抗病毒评估。在生化分析中，这种新亚型的类似物可在低纳摩尔范围内有效抑制RT RNase H，而在测试的最高浓度下却不会抑制RT聚合酶（pol）或整合酶链转移（INST）。在基于细胞的测定中，一些类似物在低微摩尔范围内抑制HIV，浓度高达100μM，却没有细胞毒性。
• 3-Hydroxypyrimidine-2,4-diones as an Inhibitor Scaffold of HIV Integrase
  作者：Jing Tang、Kasthuraiah Maddali、Mathieu Metifiot、Yuk Y. Sham、Robert Vince、Yves Pommier、Zhengqiang Wang

  DOI：10.1021/jm1014378

  日期：2011.4.14

  Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (IN Is). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.