Ethyl 3-bromo-4-[(2-chloroacetyl)amino]benzoate | 1156615-99-4

• 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: Ethyl 3-bromo-4-[(2-chloroacetyl)amino]benzoate
• CAS: 1156615-99-4
• 化学式: C₁₁H₁₁BrClNO₃
• mdl: MFCD12123488
• 分子量: 320.57
• InChiKey: ORVAXOHRQFBQJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.272
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-mesityl-1H-imidazo[4,5-c]pyridine-2-thiol 、 Ethyl 3-bromo-4-[(2-chloroacetyl)amino]benzoate 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 2.0h， 以56.7%的产率得到Ethyl 3-bromo-4-[[2-[1-(2,4,6-trimethylphenyl)imidazo[4,5-c]pyridin-2-yl]sulfanylacetyl]amino]benzoate
  参考文献：
  名称：

  Arylazolyl(azinyl)thioacetanilides. Part 10: Design, synthesis and biological evaluation of novel substituted imidazopyridinylthioacetanilides as potent HIV-1 inhibitors

  摘要：

  In continuation of our efforts toward the discovery of potent HIV-1 NNRTIs with novel structures, we have employed a scaffold hopping strategy to explore the chemically diversed space of bioactive compounds. The original arylazolylthioacetanilide platform was replaced with different imidazopyridinylthioacetanilide scaffolds to yield the optimal pharmacophore moieties in order to generate novel NNRTIs with desirable potency. Some of the new compounds proved able to inhibit HIV-1 replication in the low micromolar range. In particular, compound 5b16 displayed the most potent anti-HIV-1 activity (EC50 = 0.21 +/- 0.06 mu M), inhibiting HIV-1 IIIB replication in MT-4 cells more effectively than dideoxycytidine (EC50 = 1.4 +/- 0.1 mu M) and similarly with nevirapine (EC50 = 0.20 +/- 0.10 mu M). Preliminary structure-activity relationship (SAR) of the newly synthesized congeners is discussed, and molecular modeling study is performed to rationalize the SAR conclusions. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.07.026

文献信息

• Discovery of novel pyridazinylthioacetamides as potent HIV-1 NNRTIs using a structure-based bioisosterism approach
  作者：Yu’ning Song、Peng Zhan、Dongwei Kang、Xiao Li、Ye Tian、Zhenyu Li、Xuwang Chen、Wenmin Chen、Christophe Pannecouque、Erik De Clercq、Xinyong Liu

  DOI：10.1039/c3md00028a

  日期：——

  In continuation of our endeavors to develop new, potent, selective, and less toxic anti-HIV agents, we describe our structure-based bioisosterism design, synthetic strategy, and structure–activity relationship (SAR) studies that led to the identification of pyridazinylthioacetamides, a novel class of NNRTIs, isosteres of arylazolylthioacetanilide derivatives. Nearly all of the tested compounds inhibited HIV-1 strain IIIB replication in the lower micromolar concentration range (EC50: 0.046–5.46 μM). Notably, the most promising compound 8k exhibited extremely potent inhibitory activity against HIV-1 replication with an EC50 value of 0.046 μM, CC50 of 99.9 μM and the viral selectivity index amounted to 2149. These values were much better than those of NVP (EC50 = 0.09 μM) and DDC (EC50 = 1.04 μM). Compound 8k also exhibited moderate inhibition of enzymatic activity with an IC50 value of 4.06 μM, which was of the same order of magnitude as that of NVP (2.74 μM). Docking calculations were also performed to investigate the binding mode of compound 8k into the non-nucleoside binding site of HIV-1 RT and to rationalize some SARs.

  为了继续开发新型、强效、选择性和低毒的抗艾滋病毒药物，我们介绍了基于结构的生物异构设计、合成策略和结构-活性关系（SAR）研究，通过这些研究，我们发现了哒嗪基硫代乙酰胺类化合物，这是一类新型的 NNRTIs，是芳唑基硫代乙酰苯胺衍生物的异构体。几乎所有测试化合物都能在较低的微摩尔浓度范围内抑制 HIV-1 株 IIIB 的复制（EC50：0.046-5.46 μM）。值得注意的是，最有前途的化合物 8k 对 HIV-1 复制具有极强的抑制活性，其 EC50 值为 0.046 μM，CC50 为 99.9 μM，病毒选择性指数为 2149。这些数值远远优于 NVP（EC50 = 0.09 μM）和 DDC（EC50 = 1.04 μM）。化合物 8k 对酶活性也表现出中等程度的抑制作用，其 IC50 值为 4.06 μM，与 NVP（2.74 μM）处于同一数量级。为了研究化合物 8k 与 HIV-1 RT 非核苷结合位点的结合模式，并使一些 SARs 更加合理，还进行了对接计算。
• Arylazolyl(azinyl)thioacetanilides: Part 19: Discovery of Novel Substituted Imidazo[4,5-b]pyridin-2-ylthioacetanilides as Potent HIV NNRTIs Via a Structure-based Bioisosterism Approach
  作者：Xiao Li、Boshi Huang、Zhongxia Zhou、Ping Gao、Christophe Pannecouque、Dirk Daelemans、Erik De Clercq、Peng Zhan、Xinyong Liu

  DOI：10.1111/cbdd.12751

  日期：2016.8

  5‐b]pyridin‐2‐ylthioacetanilides were designed, synthesized, and evaluated for their antiviral activities through combining bioisosteric replacement and structure‐based drug design. Almost all of the title compounds displayed moderate to good activities against wild‐type (wt) HIV‐1 strain with EC50 values ranging from 0.059 to 1.41 μm in a cell‐based antiviral assay. Thereinto, compounds 12 and 13 were the most

  随着我们为发现有效的HIV-1 NNRTIs的不懈努力，我们设计了一系列新型咪唑并[4,5-b]吡啶-2--2-基硫代乙酰胺，并通过生物等排代用品和生物等效性评估了它们的抗病毒活性。基于结构的药物设计。几乎所有的标题化合物显示中等至对野生型（wt）HIV-1毒株具有EC良好活动50个值范围从0.059到1.41μ米在基于细胞的抗病毒测定。到其中，化合物12和13是最活跃2代的类似物具有的EC 50 0.059 0.073μ值米对抗WT HIV-1，分别，这比对照药物奈韦拉平更有效（EC 50 = 0.26μ米）并且与地拉呋啶（EC 50 = 0.038μ米）。另外，与奈韦拉平和依曲韦林相比，一种选择的化合物显示出显着的逆转录酶抑制活性。在本文的最后，详细讨论了初步的结构-活性关系（SAR）和分子建模研究，这可能为进一步优化提供有价值的见解。
• Arylazolyl(azinyl)thioacetanilides. Part 16: Structure-based bioisosterism design, synthesis and biological evaluation of novel pyrimidinylthioacetanilides as potent HIV-1 inhibitors
  作者：Xiao Li、Xueyi Lu、Wenmin Chen、Huiqing Liu、Peng Zhan、Christophe Pannecouque、Jan Balzarini、Erik De Clercq、Xinyong Liu

  DOI：10.1016/j.bmc.2014.08.001

  日期：2014.10

  A series of novel pyrimidinylthioacetanilides were designed, synthesized, and evaluated for their biological activity as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Most of the tested compounds were proved to be effective in inhibiting HIV-1 (IIIB) replication with EC50 ranging from 0.15 μM to 24.2 μM, thereinto compound 15 was the most active lead with favorable inhibitory activity against HIV-1 (IIIB) (EC50=0.15 μM, SI=684). Besides, compound 6 displayed moderate inhibition against the double-mutated HIV-1 strain (K103N/Y181C) (EC50=3.9 μM). Preliminary structure-activity relationships (SARs), structure-cytotoxicity relationships (SCRs) data, and molecular modeling studies were discussed as well, which may provide valuable insights for further optimizations.
• Arylazolyl(azinyl)thioacetanilides. Part 20: Discovery of novel purinylthioacetanilides derivatives as potent HIV-1 NNRTIs via a structure-based bioisosterism approach
  作者：Xueyi Lu、Xiao Li、Jiapei Yang、Boshi Huang、Dongwei Kang、Fabao Zhao、Zhongxia Zhou、Erik De Clercq、Dirk Daelemans、Christophe Pannecouque、Peng Zhan、Xinyong Liu

  DOI：10.1016/j.bmc.2016.07.041

  日期：2016.9

  By means of structure-based bioisosterism approach, a series of novel purinylthioacetanilide derivatives were designed, synthesized and evaluated as potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Some of the tested compounds were found to be active against wild-type (WT) HIV-1 (IIIB) with EC50 in the range of 0.78-4.46 mu M. Among them, LAD-8 displayed the most potent anti-HIV activity (EC50 = 0.78 mu M, SI = 24). In addition, LBD-6 showed moderate activity against L100I mutant (EC50 = 5.64 mu M) and double mutant strain RES056 (EC50 = 22.24 mu M). Preliminary structure-activity relationships (SARs) were discussed in detail. Molecular modeling study was used to predict the optimal conformation in the NNRTI binding site, which may play a guiding role in further rational optimization. (C) 2016 Elsevier Ltd. All rights reserved.
• Discovery of novel 2-(3-(2-chlorophenyl)pyrazin-2-ylthio)-N-arylacetamides as potent HIV-1 inhibitors using a structure-based bioisosterism approach
  作者：Peng Zhan、Wenmin Chen、Zhenyu Li、Xiao Li、Xuwang Chen、Ye Tian、Christophe Pannecouque、Erik De Clercq、Xinyong Liu

  DOI：10.1016/j.bmc.2012.09.058

  日期：2012.12

  The present work is an extension of our ongoing efforts towards the development and identification of new molecules with anti-HIV activity which have previously led to the discovery of arylazolylthioacetanilides as highly active NNRTIs. In this article, a series of 2-2-(3-(2-chlorophenyl)pyrazin-2-ylthio)-N-arylacetamide derivatives were synthesized and evaluated for in vitro anti-HIV activity. Most of the tested compounds exhibited moderate activities against wild-type HIV-1. Among them, compound 6k showed significant activity against wild-type HIV-1 with an EC50 value of 1.7 mu M, along with moderate activity against wild-type reverse transcriptase (RT). The preliminary structure-activity relationship (SAR) and docking calculations of this new series of compounds were also investigated, which may help designing more potent molecules. Crown Copyright (C) 2012 Published by Elsevier Ltd. All rights reserved.