N-[(2S)-3-hydroxy-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]-7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-[(2S)-3-hydroxy-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]-7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxamide
• 英文别名: N-[(1S)-1-(hydroxymethyl)-2-oxo-2-pyrrolidin-1-yl-ethyl]-7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxamide
• 化学式: C₁₆H₁₅F₃N₄O₅S
• 分子量: 432.38
• InChiKey: ZKMCEUXZMOQYFA-JTQLQIEISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  157
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-[(2S)-3-hydroxy-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]-7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxamide 在 二乙胺基三氟化硫 、 potassium carbonate 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 (S)-(2-(7-nitro-5-(trifluoromethyl)benzo[d]thiazol-2-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone
  参考文献：
  名称：

  硝基芳烃作为抗结核药：减少突变的立体电子调制。

  摘要：

  硝基芳烃由于具有诱变潜力，因此在药物开发中不太受欢迎。然而，已证明几种硝基芳烃是有希望的具有特定作用方式的抗结核药，即硝基咪唑和苯并噻嗪酮。这些化合物中的硝基基团在与目标靶标结合之前，通过分枝杆菌中的酶和非酶的不同机制被激活。通过全细胞筛选程序，我们确定了一种新型的硝基硝基苯并噻唑（BT）系列，其通过抑制结核分枝杆菌（Mtb）的癸烯基磷酸基-β- d-核糖2'-表异构酶（DprE1）发挥作用）。发现该铅起初是诱变的。我们为减轻致突变性所做的努力导致鉴定出6-甲基-7-硝基-5（三氟甲基）-1,3-苯并噻唑（cBTs），这是一类新型的非致突变性抗结核药，其安全性得到了改善。与硝基邻位的甲基会降低该系列的电子亲和力，因此是这些化合物的非诱变性质。此外，cBT与Mtb DprE1的复合晶体结构建立了结合模式。这项研究导致了一种新的非诱变抗结核药，并证明了硝基芳烃的诱变性质可以通过调节立体电子性质来解决。

  DOI：

  10.1002/cmdc.201500462
• 作为产物：
  描述：

  4-氯-3,5-二硝基三氟甲苯 在 盐酸 、 三乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 三氯化磷 作用下， 以 乙醇 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 29.67h， 生成 N-[(2S)-3-hydroxy-1-oxo-1-pyrrolidin-1-ylpropan-2-yl]-7-nitro-5-(trifluoromethyl)-1,3-benzothiazole-2-carboxamide
  参考文献：
  名称：

  Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase

  摘要：

  We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-beta-D-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.017

文献信息

• Discovery of benzothiazoles as antimycobacterial agents: Synthesis, structure–activity relationships and binding studies with Mycobacterium tuberculosis decaprenylphosphoryl-β-d-ribose 2′-oxidase
  作者：Sudhir Landge、Amrita B. Mullick、Kavitha Nagalapur、João Neres、Venkita Subbulakshmi、Kannan Murugan、Anirban Ghosh、Claire Sadler、Mick D. Fellows、Vaishali Humnabadkar、Jyothi Mahadevaswamy、Prakash Vachaspati、Sreevalli Sharma、Parvinder Kaur、Meenakshi Mallya、Suresh Rudrapatna、Disha Awasthy、Vasan K. Sambandamurthy、Florence Pojer、Stewart T. Cole、Tanjore S. Balganesh、Bheemarao G. Ugarkar、V. Balasubramanian、Balachandra S. Bandodkar、Manoranjan Panda、Vasanthi Ramachandran

  DOI：10.1016/j.bmc.2015.11.017

  日期：2015.12

  We report the discovery of benzothiazoles, a novel anti-mycobacterial series, identified from a whole cell based screening campaign. Benzothiazoles exert their bactericidal activity against Mycobacterium tuberculosis (Mtb) through potent inhibition of decaprenylphosphoryl-beta-D-ribose 2'-oxidase (DprE1), the key enzyme involved in arabinogalactan synthesis. Specific target linkage and mode of binding were established using co-crystallization and protein mass spectrometry studies. Most importantly, the current study provides insights on the utilization of systematic medicinal chemistry approaches to mitigate safety liabilities while improving potency during progression from an initial genotoxic hit, the benzothiazole N-oxides (BTOs) to the lead-like AMES negative, crowded benzothiazoles (cBTs). These findings offer opportunities for development of safe clinical candidates against tuberculosis. The design strategy adopted could find potential application in discovery of safe drugs in other therapy areas too. (c) 2015 Elsevier Ltd. All rights reserved.
• Nitroarenes as Antitubercular Agents: Stereoelectronic Modulation to Mitigate Mutagenicity
  作者：Sudhir Landge、Vasanthi Ramachandran、Anupriya Kumar、João Neres、Kannan Murugan、Claire Sadler、Mick D. Fellows、Vaishali Humnabadkar、Prakash Vachaspati、Anandkumar Raichurkar、Sreevalli Sharma、Sudha Ravishankar、Supreeth Guptha、Vasan K. Sambandamurthy、Tanjore S. Balganesh、Bheemarao G. Ugarkar、V. Balasubramanian、Balachandra S. Bandodkar、Manoranjan Panda

  DOI：10.1002/cmdc.201500462

  日期：2016.2

  promising antitubercular agents with specific modes of action, namely, nitroimidazoles and benzothiazinones. The nitro group in these compounds is activated through different mechanisms, both enzymatic and non‐enzymatic, in mycobacteria prior to binding to the target of interest. From a whole‐cell screening program, we identified a novel lead nitrobenzothiazole (BT) series that acts by inhibition of de

  硝基芳烃由于具有诱变潜力，因此在药物开发中不太受欢迎。然而，已证明几种硝基芳烃是有希望的具有特定作用方式的抗结核药，即硝基咪唑和苯并噻嗪酮。这些化合物中的硝基基团在与目标靶标结合之前，通过分枝杆菌中的酶和非酶的不同机制被激活。通过全细胞筛选程序，我们确定了一种新型的硝基硝基苯并噻唑（BT）系列，其通过抑制结核分枝杆菌（Mtb）的癸烯基磷酸基-β- d-核糖2'-表异构酶（DprE1）发挥作用）。发现该铅起初是诱变的。我们为减轻致突变性所做的努力导致鉴定出6-甲基-7-硝基-5（三氟甲基）-1,3-苯并噻唑（cBTs），这是一类新型的非致突变性抗结核药，其安全性得到了改善。与硝基邻位的甲基会降低该系列的电子亲和力，因此是这些化合物的非诱变性质。此外，cBT与Mtb DprE1的复合晶体结构建立了结合模式。这项研究导致了一种新的非诱变抗结核药，并证明了硝基芳烃的诱变性质可以通过调节立体电子性质来解决。