5-butoxycarbonylamino-2-cyclohexyl-6-(pyrrolidin-1-yl)-1H-benzo[d]imidazole | 1259926-60-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5-butoxycarbonylamino-2-cyclohexyl-6-(pyrrolidin-1-yl)-1H-benzo[d]imidazole
• 英文别名: MMV6887730；MMV687730；SBZ0121；Butyl [2-cyclohexyl-6-(pyrrolidin-1-yl)-1H-benzimidazol-5-yl]carbamate；butyl N-(2-cyclohexyl-6-pyrrolidin-1-yl-3H-benzimidazol-5-yl)carbamate
• CAS: 1259926-60-7
• 化学式: C₂₂H₃₂N₄O₂
• 分子量: 384.522
• InChiKey: MMGPENLTZQKVBO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  70.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,4-二硝基-5-氟苯胺 在 吡啶 、 盐酸 、 tin(II) chloride dihdyrate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 生成 5-butoxycarbonylamino-2-cyclohexyl-6-(pyrrolidin-1-yl)-1H-benzo[d]imidazole
  参考文献：
  名称：

  新型三取代苯并咪唑，靶向 Mtb FtsZ，作为新型抗结核药物

  摘要：

  通过合理的药物设计创建了新型三取代苯并咪唑文库。大量这些苯并咪唑表现出有希望的 MIC 值在 0.5-6 μg/mL (2-15 μM) 范围内，因为它们对Mtb H37Rv 菌株具有抗菌活性。此外，五种先导化合物还对具有不同耐药性的临床Mtb菌株表现出优异的活性。所有先导化合物对 Vero 细胞均未表现出明显的细胞毒性（IC 50 > 200 μM），其以剂量依赖性方式抑制Mtb FtsZ 组装。这两种先导化合物出人意料地显示出Mtb的 GTPase 活性增强FtsZ。结果强烈表明，增加的 GTPase 活性使 FtsZ 组装不稳定，从而有效抑制 FtsZ 聚合和细丝形成。分别用先导化合物处理的Mtb FtsZ 和Mtb细胞的 TEM 和 SEM 分析强烈表明，苯并咪唑铅对抑制Mtb FtsZ 组装和 Z 环形成具有新的作用机制。

  DOI：

  10.1021/jm1012006

文献信息

• Methods for in vitro—in vivo efficacy determination
  申请人：COLORADO STATE UNIVERSITY RESEARCH FOUNDATION

  公开号：US10287617B2

  公开（公告）日：2019-05-14

  The invention provides methods for determining and evaluating the in vitro-in vivo activity relationship of the efficacy of families of compounds for infectious diseases such as tuberculosis. The validity of the methods can be confirmed by evaluation of the compounds in animal models, for example, in murine models of tuberculosis. Examples of families of antibacterial compounds that can be evaluated for in vivo efficacy using the in vitro methods described herein include benzimidazoles, pyridopyrazines, pteridines, diphenyl ethers, beta-lactams, PBP inhibitors, and compounds that are non-ribonucleic acid and protein synthesis inhibitors. The methods can be used to evaluate classes of small molecule compounds and inhibitors that may be effective against any bacterial pathogen. The methods aid the identification of compounds, such as various benzimidazoles, with modes of action having activity against clinical isolates, as well as non-replicating persistent bacilli, which can therefore enhance current clinical therapeutic regimens.

  本发明提供了确定和评估化合物家族对传染性疾病（如结核病）疗效的体外-体内活性关系的方法。这些方法的有效性可以通过在动物模型中，例如在结核病小鼠模型中对化合物进行评估来证实。可使用本文所述体外方法评估体内疗效的抗菌化合物家族包括苯并咪唑类、吡啶并嗪类、蝶啶类、二苯醚类、β-内酰胺类、PBP 抑制剂以及非核糖核酸和蛋白质合成抑制剂化合物。这些方法可用于评估可能对任何细菌病原体有效的小分子化合物和抑制剂类别。这些方法有助于鉴定对临床分离菌和非复制持久性杆菌具有活性的化合物，如各种苯并咪唑类化合物，从而改进目前的临床治疗方案。
• METHODS FOR IMPROVED IN VITRO - IN VIVO EFFICACY DETERMINATION
  申请人：COLORADO STATE UNIVERSITY RESEARCH FOUNDATION

  公开号：US20180087085A9

  公开（公告）日：2018-03-29

  The invention provides methods for determining and evaluating the in vitro-in vivo activity relationship of the efficacy of families of compounds for infectious diseases such as tuberculosis. The validity of the methods can be confirmed by evaluation of the compounds in animal models, for example, in murine models of tuberculosis. Examples of families of antibacterial compounds that can be evaluated for in vivo efficacy using the in vitro methods described herein include benzimidazoles, pyridopyrazines, pteridines, diphenyl ethers, beta-lactams, PBP inhibitors, and compounds that are non-ribonucleic acid and protein synthesis inhibitors. The methods can be used to evaluate classes of small molecule compounds and inhibitors that may be effective against any bacterial pathogen. The methods aid the identification of compounds, such as various benzimidazoles, with modes of action having activity against clinical isolates, as well as non-replicating persistent bacilli, which can therefore enhance current clinical therapeutic regimens.
• [EN] 5-CARBONYLAMINO-/(SULFONAMIDO-) SUBSTITUTED BENZ IMIDAZOLES AND USE THEREOF TREATMENT OF TUBERCULOSIS<br/>[FR] BENZ IMIDAZOLES SUBSTITUÉS 5-CARBONYLAMINO-/ (SULFONAMIDO-) ET UTILISATION DE CELUI-CI ET LE TRAITEMENT DE LA TUBERCULOSE
  申请人：UNIV NEW YORK STATE RES FOUND

  公开号：WO2013142326A1

  公开（公告）日：2013-09-26

  The present invention discloses novel 5-/6- or 5-/7- substituded benzimidazoles and pharmaceutically acceptable salts thereof. Another aspect of the invention relates to their use in treating a patient infected by Mycobacterium tuberculosis or Francisella tularensis.
• [EN] METHODS FOR IMPROVED IN VITRO-IN VIVO EFFICACY DETERMINATION<br/>[FR] MÉTHODES POUR UNE DÉTERMINATION AMÉLIORÉE DE L'EFFICACITÉ IN VITRO-IN VIVO
  申请人：UNIV COLORADO STATE RES FOUND

  公开号：WO2015138611A2

  公开（公告）日：2015-09-17

  The invention provides methods for determining and evaluating the in vitro-in vivo activity relationship of the efficacy of families of compounds for infectious diseases such as tuberculosis. The validity of the methods can be confirmed by evaluation of the compounds in animal models, for example, in murine models of tuberculosis. Examples of families of antibacterial compounds that can be evaluated for in vivo efficacy using the in vitro methods described herein include benzimidazoles, pyridopyrazines, pteridines, diphenyl ethers, beta-lactams, PBP inhibitors, and compounds that are non-ribonucleic acid and protein synthesis inhibitors. The methods can be used to evaluate classes of small molecule compounds and inhibitors that may be effective against any bacterial pathogen. The methods aid the identification of compounds, such as various benzimidazoles, with modes of action having activity against clinical isolates, as well as non-replicating persistent bacilli, which can therefore enhance current clinical therapeutic regimens.
• Novel Trisubstituted Benzimidazoles, Targeting <i>Mtb</i> FtsZ, as a New Class of Antitubercular Agents
  作者：Kunal Kumar、Divya Awasthi、Seung-Yub Lee、Ilaria Zanardi、Bela Ruzsicska、Susan Knudson、Peter J. Tonge、Richard A. Slayden、Iwao Ojima

  DOI：10.1021/jm1012006

  日期：2011.1.13

  GTPase activity of Mtb FtsZ. The result strongly suggests that the increased GTPase activity destabilizes FtsZ assembly, leading to efficient inhibition of FtsZ polymerization and filament formation. The TEM and SEM analyses of Mtb FtsZ and Mtb cells, respectively, treated with a lead compound strongly suggest that lead benzimidazoles have a novel mechanism of action on the inhibition of Mtb FtsZ assembly

  通过合理的药物设计创建了新型三取代苯并咪唑文库。大量这些苯并咪唑表现出有希望的 MIC 值在 0.5-6 μg/mL (2-15 μM) 范围内，因为它们对Mtb H37Rv 菌株具有抗菌活性。此外，五种先导化合物还对具有不同耐药性的临床Mtb菌株表现出优异的活性。所有先导化合物对 Vero 细胞均未表现出明显的细胞毒性（IC 50 > 200 μM），其以剂量依赖性方式抑制Mtb FtsZ 组装。这两种先导化合物出人意料地显示出Mtb的 GTPase 活性增强FtsZ。结果强烈表明，增加的 GTPase 活性使 FtsZ 组装不稳定，从而有效抑制 FtsZ 聚合和细丝形成。分别用先导化合物处理的Mtb FtsZ 和Mtb细胞的 TEM 和 SEM 分析强烈表明，苯并咪唑铅对抑制Mtb FtsZ 组装和 Z 环形成具有新的作用机制。