1-acetyl-3,3-difluoro-5-methylindolin-2-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 1-acetyl-3,3-difluoro-5-methylindolin-2-one
• 英文别名: 1-Acetyl-3,3-difluoro-5-methylindolin-2-one；1-acetyl-3,3-difluoro-5-methylindol-2-one
• 化学式: C₁₁H₉F₂NO₂
• 分子量: 225.195
• InChiKey: XNKSXZSFNQMBIX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  37.4
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  异烟肼 、 1-acetyl-3,3-difluoro-5-methylindolin-2-one 以 乙腈 为溶剂， 反应 12.0h， 以50%的产率得到N-(2-(1,1-difluoro-2-(2-isonicotinoylhydrazinyl)-2-oxoethyl)phenyl)acetamide
  参考文献：
  名称：

  New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity

  摘要：

  Tuberculosis (TB) is one of the leading causes of death worldwide. The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) and TB-HIV co-infection are major public health challenges. The anti-TB drugs of first choice were developed more than 4 decades ago and present several adverse effects, making the treatment of TB even more complicated and the development of new chemotherapeutics for this disease imperative. In this work, we synthesized two series of new acylhydrazides and evaluated their activity against different strains of Mtb. Derivatives of isoniazid (INH) showed important anti-Mtb activity, some being more potent than all anti-TB drugs of first choice. Moreover, three compounds proved to be more potent than INH against resistant Mtb. The Ames test showed favorable results for two of these substances compared to INH, one of which presented expressly lower toxicity to HepG2 cells than that of INH. This result shows that this compound has the potential to overcome one of the main adverse effects of this drug. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.01.071
• 作为产物：
  描述：

  1-乙酰基-5-甲基吲哚-2,3-二酮 在 二乙胺基三氟化硫 作用下， 以 二氯甲烷 为溶剂， 反应 4.0h， 以95%的产率得到1-acetyl-3,3-difluoro-5-methylindolin-2-one
  参考文献：
  名称：

  伊马替尼衍生物作为慢性粒细胞白血病K562细胞抑制剂

  摘要：

  伊马替尼是用于治疗慢性粒细胞白血病的Breakpoint簇区域-Abelson鼠白血病病毒致癌基因同源物（BCR-ABL）酪氨酸激酶抑制剂类别的第一个代表。第二代和第三代药物已被引入该疗法中，从而提高了患者的生存率。但是，所有BCR-ABL酪氨酸激酶抑制剂均已显示出可诱导耐药性，因此有必要寻找新的治疗选择。舒尼替尼是一种用于治疗肾细胞癌和胃肠道间质瘤的酪氨酸激酶抑制剂。Isatin核在制备新物质方面具有很高的通用性，并且已经使用它获得了一些酪氨酸激酶抑制剂实例。这项工作旨在设计，合成，并使用组成性表达活性BCR-ABL酶的K562细胞系对新化合物进行生物学评估。已从伊马替尼计划了三个新系列的伊马替尼衍生物，所有这些衍生物均具有苯基氨基嘧啶基团作为主要药效基团。舒尼替尼被用作计划系列1（舒尼替尼和伊马替尼之间的杂种8a – e）。系列2和3分别是2-氧代-2-苯乙酰胺和2，2-二氟-2-苯基

  DOI：

  10.1007/s00044-017-1993-8

文献信息

• Imatinib derivatives as inhibitors of K562 cells in chronic myeloid leukemia
  作者：Liviane D. Azevedo、Mônica M. Bastos、Flávia C. Vasconcelos、Lucas V. B. Hoelz、Floriano P. S. Junior、Rafael F. Dantas、Ana C. M. de Almeida、Andressa Paula de Oliveira、Larissa C. Gomes、Raquel C. Maia、Nubia Boechat

  DOI：10.1007/s00044-017-1993-8

  日期：2017.11

  evaluation of new compounds using the K562 cell line, which constitutively expresses the active BCR-ABL enzyme. Three new series of imatinib derivatives have been planned from the imatinib, and all have a phenylaminopyrimidine group as the main pharmacophore. Sunitinib was used as a structural prototype to planning the series 1 (8a–e) of hybrids between sunitinib and imatinib. Series 2 and 3 are 2

  伊马替尼是用于治疗慢性粒细胞白血病的Breakpoint簇区域-Abelson鼠白血病病毒致癌基因同源物（BCR-ABL）酪氨酸激酶抑制剂类别的第一个代表。第二代和第三代药物已被引入该疗法中，从而提高了患者的生存率。但是，所有BCR-ABL酪氨酸激酶抑制剂均已显示出可诱导耐药性，因此有必要寻找新的治疗选择。舒尼替尼是一种用于治疗肾细胞癌和胃肠道间质瘤的酪氨酸激酶抑制剂。Isatin核在制备新物质方面具有很高的通用性，并且已经使用它获得了一些酪氨酸激酶抑制剂实例。这项工作旨在设计，合成，并使用组成性表达活性BCR-ABL酶的K562细胞系对新化合物进行生物学评估。已从伊马替尼计划了三个新系列的伊马替尼衍生物，所有这些衍生物均具有苯基氨基嘧啶基团作为主要药效基团。舒尼替尼被用作计划系列1（舒尼替尼和伊马替尼之间的杂种8a – e）。系列2和3分别是2-氧代-2-苯乙酰胺和2，2-二氟-2-苯基
• Antimalarial and anti-inflammatory activities of new chloroquine and primaquine hybrids: Targeting the blockade of malaria parasite transmission
  作者：Nubia Boechat、Rita C.C. Carvalho、Maria de Lourdes G. Ferreira、Julia Penna Coutinho、Paula M. Sa、Leonardo N. Seito、Elaine C. Rosas、Antoniana U. Krettli、Monica M. Bastos、Luiz C.S. Pinheiro

  DOI：10.1016/j.bmc.2020.115832

  日期：2020.12

  to reduce symptoms of infection such as fever and inflammation. A series of 21 hybrid compounds were designed from chloroquine (CQ) and primaquine (PQ) linked to the pharmacophoric group present in phenylacetic anti-inflammatory drugs. These compounds were designed to have dual activity: namely, to be capable of killing Plasmodium and still act on the inflammatory process caused by malaria infection

  疟疾是一种不仅需要抗疟原虫而且还需要减少感染症状（如发烧和发炎）的新药。从氯喹（CQ）和伯氨喹（PQ）设计了一系列21种杂化化合物，这些化合物与苯乙酸抗炎药中存在的药效基团相连。这些化合物被设计为具有双重活性：即，能够杀死疟原虫并且仍然对由疟疾感染引起的炎症过程起作用。用九种不同的生物学方法测定化合物。羰基化的CQ衍生物6（n = 3; R 1  = Cl）在体外比CQ更有效，而8（n = 4; R 1 ＝ H）在第7天将伯氏疟原虫寄生虫病降低至37％。羰基化的PQ衍生物17（R ＝ Br）的效力略低于PQ。所述宝石二氟PQ衍生物20（R = Cl）的表现出的蚊子的疟疾孢子生殖周期的高传输封锁。化合物6和20剂量依赖性地减少LPS刺激的J774A.1巨噬细胞产生的一氧化氮（NO）的产生并抑制TNFα的产生。我们的结果表明，在规划用作阻止恶性疟原虫和间日疟原虫引起的疟疾的传播阻断药物的新化学实体方面，可行且有趣的方法
• Phenylhydrazides as inhibitors of Leishmania amazonensis arginase and antileishmanial activity
  作者：Evanoel Crizanto de Lima、Frederico S. Castelo-Branco、Claudia C. Maquiaveli、André B. Farias、Magdalena N. Rennó、Nubia Boechat、Edson R. Silva

  DOI：10.1016/j.bmc.2019.07.022

  日期：2019.9

  Searching for new substances with antileishmanial activity, we synthesized and evaluated a series of alpha,alpha-difluorohydrazide and alpha,alpha-difluoramides against Leishmania amazonensis arginase (LaArg). Four alpha,alpha-difluorohydrazide derivatives showed activity against LaArg with K-i in the range of 1.3-26 mu M. The study of the kinetics of LaArg inhibition showed that these substances might act via different inhibitory mechanisms or even by a combination of these. The compounds were tested against L. amazonensis promastigotes and the best result was obtained to the compound 4 (EC50 of 12.7 +/- 0.3 mu M). In addition, in order to obtain further insight into the binding mode of such compounds, molecular docking studies were performed to obtain additional validation of experimental results. Considering these results, it is possible to conclude that alpha,alpha-difluorohydrazide derivatives are a promising scaffold in the development of new substances against the etiological agent of leishmaniasis by targeting LaArg.
• New hydrazides derivatives of isoniazid against Mycobacterium tuberculosis: Higher potency and lower hepatocytotoxicity
  作者：Frederico Silva Castelo-Branco、Evanoel Crizanto de Lima、Jorge Luiz de Oliveira Domingos、Angelo C. Pinto、Maria Cristina S. Lourenço、Karen Machado Gomes、Mariana Marques Costa-Lima、Carlos Fernando Araujo-Lima、Claudia Alessandra Fortes Aiub、Israel Felzenszwalb、Thadeu Estevam M.M. Costa、Carmen Penido、Maria G. Henriques、Nubia Boechat

  DOI：10.1016/j.ejmech.2018.01.071

  日期：2018.2

  Tuberculosis (TB) is one of the leading causes of death worldwide. The emergence of multi-drug resistant strains of Mycobacterium tuberculosis (Mtb) and TB-HIV co-infection are major public health challenges. The anti-TB drugs of first choice were developed more than 4 decades ago and present several adverse effects, making the treatment of TB even more complicated and the development of new chemotherapeutics for this disease imperative. In this work, we synthesized two series of new acylhydrazides and evaluated their activity against different strains of Mtb. Derivatives of isoniazid (INH) showed important anti-Mtb activity, some being more potent than all anti-TB drugs of first choice. Moreover, three compounds proved to be more potent than INH against resistant Mtb. The Ames test showed favorable results for two of these substances compared to INH, one of which presented expressly lower toxicity to HepG2 cells than that of INH. This result shows that this compound has the potential to overcome one of the main adverse effects of this drug. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Antiplasmodial, Trypanocidal, and Genotoxicity In Vitro Assessment of New Hybrid α,α-Difluorophenylacetamide-statin Derivatives
  作者：Carlos Fernando Araujo-Lima、Rita de Cassia Castro Carvalho、Sandra Loureiro Rosario、Debora Inacio Leite、Anna Caroline Campos Aguiar、Lizandra Vitoria de Souza Santos、Julianna Siciliano de Araujo、Kelly Salomão、Carlos Roland Kaiser、Antoniana Ursine Krettli、Monica Macedo Bastos、Claudia Alessandra Fortes Aiub、Maria de Nazaré Correia Soeiro、Nubia Boechat、Israel Felzenszwalb

  DOI：10.3390/ph16060782

  日期：——

  Background: Statins present a plethora of pleiotropic effects including anti-inflammatory and antimicrobial responses. A,α-difluorophenylacetamides, analogs of diclofenac, are potent pre-clinical anti-inflammatory non-steroidal drugs. Molecular hybridization based on the combination of pharmacophoric moieties has emerged as a strategy for the development of new candidates aiming to obtain multitarget ligands

  背景：他汀类药物具有多种多效作用，包括抗炎和抗菌反应。A,α-二氟苯乙酰胺是双氯芬酸的类似物，是有效的临床前抗炎非甾体药物。基于药效基团组合的分子杂交已成为开发旨在获得多靶点配体的新候选物的策略。方法：考虑到苯乙酰胺的抗炎活性和他汀类药物对专性细胞内寄生虫的潜在杀菌作用，本工作的目的是合成八种新的α杂合化合物，具有他汀类药物部分的 α-二氟苯乙酰胺，除了探索其遗传毒性安全性外，还评估其针对恶性疟原虫和克氏锥虫感染体外模型的表型活性。结果：钠盐化合物均未表现出抗寄生虫活性，两种醋酸化合物表现出轻微的抗寄生虫活性。恶性疟原虫效应。针对克氏锥虫，醋酸盐卤化杂种对与人类感染相关的两种寄生虫形式显示出中等效果。尽管具有相当大的杀锥虫活性，但溴化化合物显示出遗传毒性，损害了未来的体内测试。结论：然而，氯化衍生物是最有前途的化合物，具有化学和生物学有利的特性，并且在体外不存在遗传毒性，