4-(naphthalen-2-yl)-2,4-dioxobutanoic acid | 105356-61-4

• 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: 4-(naphthalen-2-yl)-2,4-dioxobutanoic acid
• 英文别名: 4-Naphthalen-2-yl-2,4-dioxobutanoic acid
• CAS: 105356-61-4
• 化学式: C₁₄H₁₀O₄
• 分子量: 242.231
• InChiKey: FKWRPGPJLOACPH-UHFFFAOYSA-N

物化性质

• 沸点：
  459.0±28.0 °C(Predicted)
• 密度：
  1.346±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  71.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(naphthalen-2-yl)-2,4-dioxobutanoic acid 在 一水合肼 、 溶剂黄146 作用下， 以82%的产率得到5-萘-2-基-1H-吡唑-3-羧酸
  参考文献：
  名称：

  5-Aryl-1H-pyrazole-3-carboxylic acids as selective inhibitors of human carbonic anhydrases IX and XII

  摘要：

  Inhibitory activity of a congeneric set of 23 phenyl-substituted 5-phenyl-pyrazole-3-carboxylic acids toward human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms I, II, IX and XII was evaluated by a stopped-flow CO2 hydrase assay. These compounds exerted a clear, selective inhibition of hCA IX and XII over hCAI and II, with Ki in two to one digit micromolar concentrations (4-50 mu M). Derivatives bearing bulkier substituents in para-position of the phenyl ring inhibited hCA XII at one-digit micromolar concentrations, while derivatives having alkyl substituents in both ortho-and meta-positions inhibited hCA IX with Kis ranging between 5 and 25 mu M. Results of docking experiments offered a rational explanation on the selectivity of these compounds toward CA IX and XII, as well as on the substitution patterns leading to best CA IX or CA XII inhibitors. By examining the active sites of these four isoforms with GRID generated molecular-interaction fields, striking differences between hCA XII and the other three isoforms were observed. The field of hydrophobic probe (DRY) appeared significantly different in CA XII active site, comparing to other three isoforms studied. To the best of our knowledge such an observation was not reported in literature so far. Considering the selectivity of these carboxylates towards membrane-associated over cytosolic CA isoforms, the title compounds could be useful for the development of isoform-specific non-sulfonamide CA inhibitors. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.05.052
• 作为产物：
  描述：

  ethyl 4-(naphthalen-2-yl)-2,4-dioxobutanoate 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 以40%的产率得到4-(naphthalen-2-yl)-2,4-dioxobutanoic acid
  参考文献：
  名称：

  新型 5(H)-phenanthridin-6-ones、5(H)-phenanthridin-6-one 二酮酸和多环芳香二酮酸类似物作为新型 HIV-1 整合酶抑制剂的合成和生物学评价。

  摘要：

  已经合成了一系列新的菲啶酮衍生物和二酮酸类似物，以及相关的菲和蒽二酮酸，并将其作为 HIV 整合酶 (IN) 抑制剂进行了评估。菲啶酮支架被菲、蒽或芘取代的几种新的 β-二酮酸类似物表现出最高的 IN 抑制效力。对整合酶链转移步骤有普遍的选择性。最有效的 IN 是 2,4-dioxo-4-phenanthren-9-yl-butyric acid (27f) 与 IC(50) 的 0.38microM 对整合酶链转移。菲二酮酸 27d-f 比相应的菲啶酮二酮酸 16 (IC(50)=65microM) 更有效 (IC(50)=2.7-0.38microM)，表明菲啶酮系统中的极性酰胺桥相对于更亲脂的菲系统降低了抑制活性。这可能与化合物的芳基可能结合到整合酶活性位点的亲脂口袋上，如对接模拟所建议的。分子模型还表明活性位点 Mg(2+) 螯合的有效性有助于 IN 抑制效力。最后，一些有效的化合物抑制

  DOI：

  10.1016/j.bmc.2006.11.026

文献信息

• Synthesis, antimicrobial activity, structure-activity relationship and cytotoxic studies of a new series of functionalized (Z)-3-(2-oxo-2-substituted ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones
  作者：Ritu Sharma、Lalit Yadav、Jaggi Lal、Pradeep K. Jaiswal、Manas Mathur、Ajit K. Swami、Sandeep Chaudhary

  DOI：10.1016/j.bmcl.2017.08.017

  日期：2017.9

  ethylidene)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-ones 23–26, incorporating pharmaceutically privileged substructures such as cyclopropyl, naphthyl, biphenyl and cyclohexylphenyl were synthesized in excellent yields. All the synthesized compounds were screened for their in vitro antibacterial activity against gram-(+)ve and gram-(−)ve bacterial species i.e. S. griseus, S. aureus, B. subtillis and E. coli as

  一系列新的官能化（Z）-3-（2-氧-2-取代亚乙基）-3,4-二氢-2 H-苯并[ b ] [1,4]恶嗪-2-酮23 – 26，以优异的产率合成了药学上优先的亚结构，例如环丙基，萘基，联苯和环己基苯基。所有合成的化合物筛选它们体外抗革兰氏抗菌活性- （+）ve和克- （ - ）已经细菌物种即灰色链霉菌，金黄色葡萄球菌，枯草芽孢杆菌和大肠杆菌以及体外抗真菌对真菌物种，即氧化枯萎病菌的活性，A。niger，P。funiculosum和T. reesei。在这项研究中，与标准药物，氨苄青霉素和氯霉素以及酮康唑相比，含有环丙基和环己基苯基亚结构的化合物被确定为有前途的抗菌剂。SAR研究表明，吸电子基团增加了2-氧代-苯并[1,4]恶嗪的抗菌和抗真菌活性，反之亦然。该系列中活性最高的化合物23e和26e比氨苄青霉素和氯霉素显示出令人鼓舞的抗菌活性。此外，化合物26d与酮康唑相比，它显示出有希望的抗真菌效力。使用MTT分析法对3T
• [EN] ISPH INHIBITORS, AND METHODS OF MAKING AND USING SAME<br/>[FR] INHIBITEURS D'ISPH, ET LEURS PROCÉDÉS DE FABRICATION ET D'UTILISATION
  申请人：THE WISTAR INST

  公开号：WO2021021933A1

  公开（公告）日：2021-02-04

  In one aspect, the invention provides novel compounds useful for treating bacterial infections, such as but not limited to Gram-negative bacterial infections. In another aspect, the invention provides novel compounds useful for activating γδ T cell response during bacterial infections, such as but not limited to infections with Helicobacter pylori. In certain embodiments, the compounds of the invention are IspH inhibitors.

  本发明提供了用于治疗细菌感染的新型化合物，例如但不限于革兰氏阴性细菌感染。在另一个方面，本发明提供了用于在细菌感染期间激活γδT细胞反应的新型化合物，例如但不限于幽门螺杆菌感染。在某些实施例中，本发明的化合物是IspH抑制剂。
• RETRACTED ARTICLE: IspH inhibitors kill Gram-negative bacteria and mobilize immune clearance
  作者：Kumar Sachin Singh、Rishabh Sharma、Poli Adi Narayana Reddy、Prashanthi Vonteddu、Madeline Good、Anjana Sundarrajan、Hyeree Choi、Kar Muthumani、Andrew Kossenkov、Aaron R. Goldman、Hsin-Yao Tang、Maxim Totrov、Joel Cassel、Maureen E. Murphy、Rajasekharan Somasundaram、Meenhard Herlyn、Joseph M. Salvino、Farokh Dotiwala

  DOI：10.1038/s41586-020-03074-x

  日期：2021.1.28

  Isoprenoids are vital for all organisms, in which they maintain membrane stability and support core functions such as respiration1. IspH, an enzyme in the methyl erythritol phosphate pathway of isoprenoid synthesis, is essential for Gram-negative bacteria, mycobacteria and apicomplexans2,3. Its substrate, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), is not produced in metazoans, and in humans and other primates it activates cytotoxic Vγ9Vδ2 T cells at extremely low concentrations4–6. Here we describe a class of IspH inhibitors and refine their potency to nanomolar levels through structure-guided analogue design. After modification of these compounds into prodrugs for delivery into bacteria, we show that they kill clinical isolates of several multidrug-resistant bacteria—including those from the genera Acinetobacter, Pseudomonas, Klebsiella, Enterobacter, Vibrio, Shigella, Salmonella, Yersinia, Mycobacterium and Bacillus—yet are relatively non-toxic to mammalian cells. Proteomic analysis reveals that bacteria treated with these prodrugs resemble those after conditional IspH knockdown. Notably, these prodrugs also induce the expansion and activation of human Vγ9Vδ2 T cells in a humanized mouse model of bacterial infection. The prodrugs we describe here synergize the direct killing of bacteria with a simultaneous rapid immune response by cytotoxic γδ T cells, which may limit the increase of antibiotic-resistant bacterial populations. A class of compounds with a dual mechanism of action—direct targeting of IspH and stimulation of cytotoxic γδ T cells to enhance pathogen clearance—are active against multidrug-resistant bacteria.

  异丙肾上腺素对所有生物都至关重要，它们能维持膜的稳定性并支持呼吸等核心功能1。IspH 是异戊二烯合成途径中赤藓醇磷酸甲酯途径的一种酶，对革兰氏阴性菌、分枝杆菌和类鼻疽杆菌至关重要2,3。它的底物(E)-4-羟基-3-甲基-丁-2-烯基焦磷酸（HMBPP）在元类动物中不产生，而在人类和其他灵长类动物中，它能在极低浓度下激活细胞毒性 Vδ9Vδ2 T 细胞4â6。在这里，我们描述了一类 IspH 抑制剂，并通过结构引导的类似物设计将其药效提高到纳米级水平。我们将这些化合物改性为原药，并将其输送到细菌体内，结果表明，它们能杀死多种耐多药细菌的临床分离株，包括不动杆菌属、假单胞菌属、克雷伯氏菌属、肠杆菌属、弧菌属、志贺氏菌属、沙门氏菌属、耶尔森氏菌属、分枝杆菌属和芽孢杆菌属的细菌，但对哺乳动物细胞相对无毒。蛋白质组分析表明，使用这些原药处理的细菌与条件性 IspH 基因敲除后的细菌相似。值得注意的是，在人源化小鼠细菌感染模型中，这些原药还能诱导人类 Vδ9Vδ2 T 细胞的扩增和活化。我们在此介绍的这些原药在直接杀灭细菌的同时，还能协同细胞毒性δδT 细胞产生快速免疫反应，这可能会限制抗生素耐药细菌数量的增加。一类具有双重作用机制（直接靶向 IspH 和刺激细胞毒性 δδ´ T 细胞以提高病原体清除率）的化合物对多重耐药细菌具有活性。
• [EN] HIV INTEGRASE INHIBITORS<br/>[FR] INHIBITEURS DE VIH INTEGRASE
  申请人：MERCK & CO., INC.

  公开号：WO1999062520A1

  公开（公告）日：1999-12-09

  (EN) Certain six-membered aromatic and heteroaromatic-dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.(FR) Cette invention a trait à certains dérivés d'acide dioxo-butyrique à 6 chaînons, aromatique et hétéro-aromatique, agissant en tant qu'inhibiteurs de VIH intégrase et de la réplication du VIH. Ces composés sont utilisés dans le cadre de la prévention et du traitement des infections par le VIH et du sida, que ce soit sous forme de composés, de sels acceptables du point de vue pharmaceutique ou d'ingrédients de composition pharmaceutique, seuls ou associés à d'autres antiviraux, immunorégulateurs, antibiotiques ou vaccins. L'invention concerne également des méthodes de traitement du sida ainsi que des méthodes de prévention et de traitement des infections par VIH.

  某些六元芳香和杂芳二酮丁酸衍生物被描述为HIV整合酶抑制剂和HIV复制抑制剂。这些化合物可用于预防或治疗HIV感染和治疗艾滋病，无论是作为化合物、药学上可接受的盐、药物组成成分，还是与其他抗病毒药物、免疫调节剂、抗生素或疫苗联合使用。还描述了治疗艾滋病的方法以及预防或治疗HIV感染的方法。
• Synthesis, Intramolecular Cyclization, and Analgesic Activity of Substituted 2-[2-(Furancarbonyl)hydrazinylydene]-4-oxobutanoic Acids
  作者：S. N. Igidov、A.Yu. Turyshev、R. R. Makhmudov、D. A. Shipilovskikh、N. M. Igidov、S. A. Shipilovskikh

  DOI：10.1134/s1070363222090067

  日期：2022.9

  proposed for the synthesis of substituted 2-[2-(furan-2-carbonyl)hydrazinylidene]-4-oxobutanoic acids by the reaction of 4-aryl-2,4-dioxobut-2-enoic acids with furan-2-carbohydrazide. It was found that substituted 2-[2-(furan-2-carbonyl)hydrazinylidene]-4-oxobutanoic acids undergo intramolecular cyclization in the presence of propionic anhydride to form the corresponding substituted 2-[2-(furan-2-carbonyl

  摘要 提出了一种由4-aryl-2,4-dioxobut-2-enoic酸与furan-2反应合成取代的2-[2-(furan-2-carbonyl)hydrazinylidene]-4-oxobutanoic酸的方法。 -碳酰肼。发现取代的2-[2-(呋喃-2-羰基)亚肼基]-4-氧代丁酸在丙酸酐存在下发生分子内环化形成相应的取代的2-[2-(呋喃-2-羰基)亚肼基]-4-氧代丁酸。对所得化合物的镇痛活性和急性毒性进行了研究，发现所得化合物具有显着的镇痛活性和低毒性。根据药物毒性分类，生成的取代的2-[2-(呋喃-2-羰基)亚肼基]-4-氧代丁酸和2-[5-芳基-2-氧代呋喃-3(2 H)-亚叉基]furan-2-carbohydrazides属于V类几乎无毒的药物。