ELQ-271 | 1354745-32-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: ELQ-271
• 英文别名: 2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one；2-methyl-3-{4-[4-(trifluoromethoxy)phenoxy]phenyl}quinolin-4(1H)-one；2-methyl-3-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1H-quinolin-4-one
• CAS: 1354745-32-6
• 化学式: C₂₃H₁₆F₃NO₃
• 分子量: 411.38
• InChiKey: RKMHINMEXBCMOM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  47.6
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ELQ-271 在 selenium(IV) oxide 、 potassium tert-butylate 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 6.5h， 生成 ethyl (2-formyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4-yl)carbonate
  参考文献：
  名称：

  靶向恶性疟原虫 II 型 NADH:醌氧化还原酶 (PfNDH2) 的双芳基喹诺酮类药物的鉴定、设计和生物学评价

  摘要：

  进行了一项计划来鉴定针对 NADH 的命中化合物：泛醌氧化还原酶 (PfNDH2)，这是一种疟疾寄生虫恶性疟原虫线粒体电子传递链的脱氢酶. PfNDH2 只有一种已知抑制剂，羟基-2-十二烷基-4-(1H)-喹诺酮 (HDQ)，它与一系列化学信息学方法一起用于合理选择 17000 种化合物以进行高通量筛选。确定并简要检查了 12 种不同的化学型，导致选择喹诺酮核心作为构效关系 (SAR) 发展的关键目标。广泛的结构探索导致选择 2-双芳基 3-甲基喹诺酮作为进一步生物学评价的系列。该系列中的先导化合物 7-chloro-3-methyl-2-(4-(4-(trifluoromethoxy)benzyl)phenyl)quinolin-4(1H)-one (CK-2-68) 对 3D7 具有抗疟活性36 nM 的恶性疟原虫菌株对 PfNDH2 的选择性高于其他呼吸酶（抑制性 IC50对 PfNDH2

  DOI：

  10.1021/jm201179h
• 作为产物：
  描述：

  4-ethoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline 在 氢溴酸 、 溶剂黄146 作用下， 以 水 为溶剂， 反应 24.0h， 以84%的产率得到ELQ-271
  参考文献：
  名称：

  Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

  摘要：

  The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

  DOI：

  10.1021/jm500147k

文献信息

• New Scalable Synthetic Routes to <b>ELQ-300</b>, <b>ELQ-316</b>, and Other Antiparasitic Quinolones
  作者：Sovitj Pou、Rozalia A. Dodean、Lisa Frueh、Katherine M. Liebman、Rory T. Gallagher、Haihong Jin、Robert T. Jacobs、Aaron Nilsen、David R. Stuart、J. Stone Doggett、Michael K. Riscoe、Rolf W. Winter

  DOI：10.1021/acs.oprd.1c00099

  日期：2021.8.20

  series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad–Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first

  内啡肽样喹诺酮 (ELQ) 化合物类可以为一系列重要的人类和动物疾病提供有效、安全的治疗方法。然而，为了获得该化合物系列的公共卫生潜力，需要设计一种合成路线，该路线将降低成本并适合大规模生产。在这里描述的新合成路线中，通过 Ullmann 反应和随后的酰化形成取代的 β-酮酯，通过 Conrad-Limpach 反应与苯胺反应生成 3-取代的 4( 1H )-喹诺酮类，例如ELQ -300和ELQ-316. 该合成路线首次被描述为真正适合工业规模生产，相对较短（五个反应步骤），不需要钯、色谱分离或保护基化学，并且可以在没有高真空蒸馏的情况下进行。
• [EN] COMPOUNDS AND METHODS FOR TREATING, DETECTING, AND IDENTIFYING COMPOUNDS TO TREAT APICOMPLEXAN PARASITIC DISEASES<br/>[FR] COMPOSÉS ET MÉTHODES DE TRAITEMENT, DE DÉPISTAGE, ET D'IDENTIFICATION DE COMPOSÉS DESTINÉS À TRAITER LES MALADIES PROVOQUÉES PAR DES PARASITES APICOMPLEXES
  申请人：MCLEOD RIMA

  公开号：WO2017112678A1

  公开（公告）日：2017-06-29

  Disclosed herein; are novel compounds for treating apicomplexan parasite related disorders, methods for their use; cell line and non-human animal models of the dormant parasite phenotype and methods for their use in identifying new drugs to teat apicomplexan parasite related disorders, and biomarkers to identify disease due to the parasite and its response to treatment.

  本公开的内容包括：用于治疗顶复合体寄生虫相关疾病的新化合物，其使用方法；休眠寄生虫表型的细胞系和非人类动物模型，以及用于识别新药物治疗顶复合体寄生虫相关疾病的方法，以及用于识别由寄生虫引起的疾病及其对治疗的反应的生物标志物。
• [EN] SYNTHESIS OF ENDOCHIN-LIKE QUINOLONES<br/>[FR] SYNTHÈSE DE QUINOLONES DE TYPE ENDOCHINE
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2022197979A1

  公开（公告）日：2022-09-22

  Described herein are new synthetic routes for production of Endochin-Like Quinolone (ELQ) compounds. Synthetic routes to 3-substituted 4(1H)-quinolones are presented that are amenable to industrial scale preparation. One herein presented approach is relatively short, does not require palladium, and involves no chromatographic separation. A second herein presented approach is similarly relatively short, does not require palladium, involves no chromatographic separation, and also avoids high vacuum distillation. Additionally, both approaches require no protecting group chemistry because the insoluble 4(1H)-quinolone is not formed until the final reaction step.

  本文介绍了新的合成路线，用于生产类内酰胺类喹啉酮（ELQ）化合物。介绍了适用于工业规模制备的3-取代4（1H）-喹啉酮的合成路线。其中一个方法相对较短，不需要钯，并且不涉及色谱分离。另一个方法同样相对较短，不需要钯，也不涉及色谱分离，并且避免了高真空蒸馏。此外，这两种方法都不需要保护基化学，因为不溶性的4（1H）-喹啉酮直到最后的反应步骤才形成。
• Combination of respiratory electron transport chain inhibitors with a cytochrome bd inhibitor
  申请人：Liverpool School of Tropical Medicine

  公开号：US10799494B2

  公开（公告）日：2020-10-13

  The present invention relates to a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors and a cytochrome bd inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising the combination therapeutic product and to the use of the combination therapeutic product in the treatment of mycobacterial infections, such as tuberculosis.

  本发明涉及一种包含一种或多种呼吸电子传递链抑制剂和细胞色素bd抑制剂（如本文所定义）或其药学上可接受的盐的组合治疗产品。本发明还涉及包含该组合治疗产品的药物组合物，以及该组合治疗产品在治疗结核病等分枝杆菌感染中的用途。
• COMBINATION PRODUCT
  申请人：Liverpool School of Tropical Medicine

  公开号：US20190151305A1

  公开（公告）日：2019-05-23

  The present invention relates to a combination therapeutic product comprising one or more respiratory electron transport chain inhibitors and a cytochrome bd inhibitor, as defined herein, or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising the combination therapeutic product and to the use of the combination therapeutic product in the treatment of mycobacterial infections, such as tuberculosis.