6-(4-fluorobenzyl)-1-((4-fluorobenzyloxy)methyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione | 1254831-92-9

• 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-(4-fluorobenzyl)-1-((4-fluorobenzyloxy)methyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione
• 英文别名: 1-[(4-Fluorophenyl)methoxymethyl]-6-[(4-fluorophenyl)methyl]-5-propan-2-ylpyrimidine-2,4-dione
• CAS: 1254831-92-9
• 化学式: C₂₂H₂₂F₂N₂O₃
• 分子量: 400.425
• InChiKey: HHPBNKUYXCHFFC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 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：
  58.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  6-(4-fluorobenzyl)-1-((4-fluorobenzyloxy)methyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione 在 sodium hydride 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 以72%的产率得到6-(4-fluorobenzyl)-1-((4-fluorobenzyloxy)methyl)-3-hydroxy-5-isopropylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase

  摘要：

  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.

  DOI：

  10.1021/ml1002162
• 作为产物：
  描述：

  2-溴代异戊酸乙酯 在 N,O-双三甲硅基乙酰胺 、 potassium tert-butylate 、 碘 、 四丁基碘化铵 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 异丙醇 为溶剂， 生成 6-(4-fluorobenzyl)-1-((4-fluorobenzyloxy)methyl)-5-isopropylpyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  N-3 Hydroxylation of Pyrimidine-2,4-diones Yields Dual Inhibitors of HIV Reverse Transcriptase and Integrase

  摘要：

  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.

  DOI：

  10.1021/ml1002162

文献信息

• 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.
• [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.
• 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.