methyl 1-(4-aminobenzoyl)piperidine-4-carboxylate | 1017621-79-2

• 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: methyl 1-(4-aminobenzoyl)piperidine-4-carboxylate
• CAS: 1017621-79-2
• 化学式: C₁₄H₁₈N₂O₃
• 分子量: 262.309
• InChiKey: CICIJIJLIAWZIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 1-(4-aminobenzoyl)piperidine-4-carboxylate 在 N,N-二甲基苯胺 作用下， 以 N,N-二甲基乙酰胺 为溶剂， 反应 188.0h， 生成 Methyl 1-[4-[(2,4-diaminopteridin-6-yl)methyl-(2-hydroxyethyl)amino]benzoyl]piperidine-4-carboxylate
  参考文献：
  名称：

  Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors

  摘要：

  The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]-piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.

  DOI：

  10.1021/jm300563f
• 作为产物：
  描述：

  4-哌啶甲酸甲酯 在 氢气 、 钯 、 三乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、303.99 kPa 条件下， 反应 1.0h， 生成 methyl 1-(4-aminobenzoyl)piperidine-4-carboxylate
  参考文献：
  名称：

  Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors

  摘要：

  The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]-piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.

  DOI：

  10.1021/jm300563f

文献信息

• Multitarget, Selective Compound Design Yields Potent Inhibitors of a Kinetoplastid Pteridine Reductase 1
  作者：Ina Pöhner、Antonio Quotadamo、Joanna Panecka-Hofman、Rosaria Luciani、Matteo Santucci、Pasquale Linciano、Giacomo Landi、Flavio Di Pisa、Lucia Dello Iacono、Cecilia Pozzi、Stefano Mangani、Sheraz Gul、Gesa Witt、Bernhard Ellinger、Maria Kuzikov、Nuno Santarem、Anabela Cordeiro-da-Silva、Maria P. Costi、Alberto Venturelli、Rebecca C. Wade

  DOI：10.1021/acs.jmedchem.2c00232

  日期：2022.7.14

  antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure–activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective

  具有多个目标的化合物的优化是药物发现周期中一个困难的多维问题。在这里，我们提出了一种系统的、多学科的方法来开发选择性抗寄生虫化合物。新型蝶啶衍生物的基于计算片段的设计以及晶体结构确定的迭代允许推导多靶点抑制的结构-活性关系。该方法产生的化合物显示出对布氏蝶啶还原酶 1 (PTR1) 的明显皮摩尔抑制，对L. major的纳摩尔抑制PTR1，以及对寄生虫二氢叶酸还原酶 (DHFR) 与人类 DHFR 的选择性亚微摩尔抑制。此外，通过将多药理学设计与基于特性的寄生虫优化相结合，我们发现三种化合物对布氏布氏锥虫表现出微摩尔 EC 50值，同时保持其目标抑制作用。我们的结果为进一步开发基于蝶啶的化合物提供了基础，我们希望我们的多靶点方法普遍适用于抗感染药物的设计和优化。
• [EN] SPECIFIC INHIBITORS OF PTERIDINE REDUCTASE WITH ANTIPARASITIC ACTION<br/>[FR] INHIBITEURS SPÉCIFIQUES DE LA PTÉRIDINE RÉDUCTASE À ACTION ANTIPARASITAIRE
  申请人：TYDOCKPHARMA S R L

  公开号：WO2009080367A3

  公开（公告）日：2009-09-11
• SPECIFIC INHIBITORS OF PTERIDINE REDUCTASE WITH ANTIPARASITIC ACTION
  申请人：Tydock Pharma S.r.l.

  公开号：EP2234998A2

  公开（公告）日：2010-10-06
• Structure-Based Selectivity Optimization of Piperidine–Pteridine Derivatives as Potent Leishmania Pteridine Reductase Inhibitors
  作者：Paola Corona、Federica Gibellini、Andrea Cavalli、Puneet Saxena、Antonio Carta、Mario Loriga、Rosaria Luciani、Giuseppe Paglietti、Davide Guerrieri、Erika Nerini、Shreedhara Gupta、Véronique Hannaert、Paul A. M. Michels、Stefania Ferrari、Paola M. Costi

  DOI：10.1021/jm300563f

  日期：2012.10.11

  The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides a salvage pathway that bypasses dihydrofolate reductase (DHFR) inhibition. The structure-based optimization of the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]-piperidine-4-carboxylate (1) led to the synthesis of a focused compound library which showed significantly improved selectivity for the parasite's folate-dependent enzyme. When used in combination with pyrimethamine, a DHFR inhibitor, a synergistic effect was observed for compound 5b. This work represents a step forward in the identification of effective antileishmania agents.