5,6-二羟基-2-噻吩-2-基-嘧啶-4-羧酸甲酯 | 391680-92-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 中文名称: 5,6-二羟基-2-噻吩-2-基-嘧啶-4-羧酸甲酯
• 中文别名: 5,6-二羟基-2-噻吩-2-基-嘧啶-4-甲酸甲酯
• 英文名称: methyl 5,6-dihydroxy-2-thien-2-ylpyrimidine-4-carboxylate
• 英文别名: 5,6-Dihydroxy-2-thiophen-2-yl-pyrimidine-4-carboxylic acid methyl ester；methyl 5-hydroxy-6-oxo-2-thiophen-2-yl-1H-pyrimidine-4-carboxylate
• CAS: 391680-92-5
• 化学式: C₁₀H₈N₂O₄S
• 分子量: 252.251
• InChiKey: QAIMSDCSXBBWEK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  116
• 氢给体数：
  2
• 氢受体数：
  6

制备方法与用途

核酸内切酶-IN-1（化合物13d）是人巨细胞病毒（HCMV）pUL89内切酶的有效抑制剂，其IC50值为0.88 μM，并具有抗病毒活性。

反应信息

• 作为反应物：
  描述：

  5,6-二羟基-2-噻吩-2-基-嘧啶-4-羧酸甲酯 在 palladium on activated charcoal 吡啶 、 lithium hydroxide 、 氢气 、 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 生成 5-Hydroxy-2-thiophen-2-yl-pyrimidine-4-carboxylic acid
  参考文献：
  名称：

  Active site inhibitors of HCV NS5B polymerase. The development and pharmacophore of 2-thienyl-5,6-dihydroxypyrimidine-4-carboxylic acid

  摘要：

  5,6-Dihydroxypyrimidine-4-carboxylic acids are a promising series of hepatitis C virus (HCV) NS5B polymerase inhibitors that bind at the active site of the enzyme. Here we report a simple 2-thienyl substituted analogue that shows 10-fold improved activity over the original lead, and which allowed us to further delineate the key elements of the pharmacophore of this class of inhibitor. This work led to the identification of a trifluoromethyl acylsulfonamide group as a viable replacement for the C4 carboxylic acid in this series. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.07.075
• 作为产物：
  描述：

  dimethyl 2-((((Z)-amino(thiophen-2-yl)methylene)amino)oxy)but-2-enedioate 以 xylene 为溶剂， 生成 5,6-二羟基-2-噻吩-2-基-嘧啶-4-羧酸甲酯
  参考文献：
  名称：

  2-(2-Thienyl)-5,6-dihydroxy-4-carboxypyrimidines as Inhibitors of the Hepatitis C Virus NS5B Polymerase:  Discovery, SAR, Modeling, and Mutagenesis

  摘要：

  Infections caused by hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The polymerase of HCV is responsible for the replication of viral RNA. We recently disclosed dihydroxypyrimidine carboxylates 2 as novel, reversible inhibitors of the HCV NS5B polymerase. This series was further developed into 5,6-dihydroxy-2-(2-thienyl)pyrimidine-4-carboxylic acids such as 34 (EC50 9.3 mu M), which now show activity in the cell-based HCV replication assay. The structure-activity relationship of these inhibitors is discussed in the context of their physicochemical properties and of the polymerase crystal structure. We also report the results of mutagenesis experiments which support the proposed binding model, which involves pyrophosphate-like chelation of the active site Mg ions.

  DOI：

  10.1021/jm051064t

文献信息

• Pharmacophore requirements for HIV-1 reverse transcriptase inhibitors that selectively “Freeze” the pre-translocated complex during the polymerization catalytic cycle
  作者：Cyrus M. Lacbay、Michael Menni、Jean A. Bernatchez、Matthias Götte、Youla S. Tsantrizos

  DOI：10.1016/j.bmc.2018.02.017

  日期：2018.5

  Reverse transcriptase (RT) is responsible for replicating the HIV-1 genome and is a validated therapeutic target for the treatment of HIV infections. During each cycle of the RT-catalyzed DNA polymerization process, inorganic pyrophosphate is released as the by-product of nucleotide incorporation. Small molecules were identified that act as bioisosteres of pyrophosphate and can selectively freeze the

  逆转录酶（RT）负责复制HIV-1基因组，并且是经验证的治疗HIV感染的治疗靶标。在RT催化的DNA聚合过程的每个循环中，无机焦磷酸盐作为核苷酸掺入的副产物释放。鉴定出的小分子充当焦磷酸盐的生物等排体，并且可以在DNA或RNA模板引物酶复合物的预易位阶段选择性冻结HIV-1 RT的催化循环。
• Dihydroxypyrimidine-4-carboxamides as Novel Potent and Selective HIV Integrase Inhibitors
  作者：Paola Pace、M. Emilia Di Francesco、Cristina Gardelli、Steven Harper、Ester Muraglia、Emanuela Nizi、Federica Orvieto、Alessia Petrocchi、Marco Poma、Michael Rowley、Rita Scarpelli、Ralph Laufer、Odalys Gonzalez Paz、Edith Monteagudo、Fabio Bonelli、Daria Hazuda、Kara A. Stillmock、Vincenzo Summa

  DOI：10.1021/jm070027u

  日期：2007.5.1

  chemotherapeutic intervention in the treatment of AIDS that has also recently been confirmed in the clinical setting. We report here on the design and synthesis of N-benzyl-5,6-dihydroxypyrimidine-4-carboxamides as a class of agents which exhibits potent inhibition of the HIV-integrase-catalyzed strand transfer process. In the current study, structural modifications on these molecules were made in order

  人类免疫缺陷病毒1型（HIV-1）整合酶是复制所需的三种组成型病毒酶之一，是化学疗法干预AIDS的合理靶标，最近在临床环境中也得到了证实。我们在这里报告的N-苄基5,6-二羟基嘧啶-4-羧酰胺的设计和合成作为一类药物，对HIV整合酶催化的链转移过程具有有效的抑制作用。在当前的研究中，对这些分子进行了结构修饰，以检查其对HIV整合酶抑制效能的影响。该系列中最有趣的化合物之一是2- [1-（二甲基氨基）-1-甲基乙基] -N-（4-氟苄基）-5,6-二羟基嘧啶-4-羧酰胺38，CIC95为78 nM。在血清蛋白存在下进行基于细胞的测定。
• Dihydroxypyrimidine carboxylic acids as viral polymerase inhibitors
  申请人：——

  公开号：US20040106627A1

  公开（公告）日：2004-06-03

  A class of 2-aryl-4,5-dihydroxy-6-carboxypyrimidines of formula (I): wherein Ar is an optionally substituted aryl or heterocyclic group; as well as compounds of formula (I) which are derivatised at one or more of the 4-hydroxy, 5-hydroxy or 6-carboxy groups; and tautomers thereof, and pharmaceutically acceptable salts or esters thereof; and inhibitors of viral polymerases, especially the hepatitis C virus (HCV) polymerase enzyme. 1

  2-芳基-4,5-二羟基-6-羧基嘧啶的一类化合物的化学式(I)：其中Ar是一个可选择地取代的芳基或杂环基；以及在4-羟基、5-羟基或6-羧基中的一个或多个位置衍生的化合物的化学式(I)；以及它们的互变异构体，以及它们的药用盐或酯；以及病毒聚合酶抑制剂，特别是乙型肝炎病毒（HCV）聚合酶酶。
• 4,5-Dihydroxypyrimidine Methyl Carboxylates, Carboxylic Acids, and Carboxamides as Inhibitors of Human Cytomegalovirus pUL89 Endonuclease
  作者：Tianyu He、Tiffany C. Edwards、Jiashu Xie、Hideki Aihara、Robert J. Geraghty、Zhengqiang Wang

  DOI：10.1021/acs.jmedchem.2c00203

  日期：2022.4.14

  Human cytomegalovirus (HCMV) terminase complex entails a metal-dependent endonuclease at the C-terminus of pUL89 (pUL89-C). We report herein the design, synthesis, and characterization of dihydroxypyrimidine (DHP) acid (14), methyl ester (13), and amide (15) subtypes as inhibitors of HCMV pUL89-C. All analogs synthesized were tested in an endonuclease assay and a thermal shift assay (TSA) and subjected

  人巨细胞病毒 (HCMV) 末端酶复合物在 pUL89 (pUL89-C) 的 C 末端包含金属依赖性核酸内切酶。我们在此报告了二羟基嘧啶 (DHP) 酸 ( 14 )、甲酯 ( 13 ) 和酰胺 ( 15 ) 亚型作为 HCMV pUL89-C 抑制剂的设计、合成和表征。所有合成的类似物都在核酸内切酶测定和热位移测定 (TSA) 中进行测试，并进行分子对接以预测结合亲和力。尽管从所有三种亚型中鉴定出在亚 μM 范围内抑制 pUL89-C 的类似物，但酸 ( 14 ) 显示出比酯 ( 13 ) 和酰胺 ( 15 ) 更好的整体效力、显着更大的热位移和更好的对接分数). 在基于细胞的抗病毒试验中，六种类似物以中等活性抑制 HCMV (EC 50 = 14.4–22.8 μM)。酸亚型 ( 14 ) 表现出良好的体外ADME 特性，但渗透性较差。总体而言，我们的数据支持 DHP 酸亚型 ( 14
• [EN] DIHYDROXYPYRIMIDINE CARBOXAMIDE INHIBITORS OF HIV INTEGRASE<br/>[FR] INHIBITEURS DE L'INTEGRASE DU VIH A BASE DE DIHYDROXYPYRIMIDINE CARBOXAMIDE
  申请人：ANGELETTI P IST RICHERCHE BIO

  公开号：WO2003035076A1

  公开（公告）日：2003-05-01

  4,5-Dihydroxypyrimidine-6-carboxamides of formula (I); are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R?1, R2, R3 and R4¿ are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

  公式为（I）的4,5-二羟基嘧啶-6-羧酰胺被描述为HIV整合酶抑制剂和HIV复制抑制剂，其中R?1，R2，R3和R4¿在此定义。这些化合物对于预防和治疗HIV感染以及预防、延迟发病和治疗艾滋病非常有用。这些化合物作为化合物本身或药物可接受的盐的形式用于对抗HIV感染和艾滋病。这些化合物及其盐可作为药物组合中的成分，可选地与其他抗病毒药物、免疫调节剂、抗生素或疫苗组合使用。还描述了预防、治疗或延迟艾滋病发病的方法以及预防或治疗HIV感染的方法。