N-(4-fluorobenzyl)-2-[(2,4-dichlorophenyl)thio]propanamide | 1418283-07-4

• 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: N-(4-fluorobenzyl)-2-[(2,4-dichlorophenyl)thio]propanamide
• 英文别名: MBX 2164；2-(2,4-dichlorophenyl)sulfanyl-N-[(4-fluorophenyl)methyl]propanamide
• CAS: 1418283-07-4
• 化学式: C₁₆H₁₄Cl₂FNOS
• 分子量: 358.264
• InChiKey: AKPANXSFWRJHJI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  54.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N-(4-fluorobenzyl)-2-[(2,4-dichlorophenyl)thio]propanamide 在 间氯过氧苯甲酸 作用下， 以 氯仿 为溶剂， 反应 16.0h， 以68%的产率得到N-(4-fluorobenzyl)-2-[(2,4-dichlorophenyl)sulfonyl]propanamide
  参考文献：
  名称：

  Synthesis and structure–activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS)

  摘要：

  The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1 mu M. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.011
• 作为产物：
  描述：

  2,4-二氯苯硫酚 在 水 、 potassium carbonate 、 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 N-(4-fluorobenzyl)-2-[(2,4-dichlorophenyl)thio]propanamide
  参考文献：
  名称：

  Synthesis and structure–activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS)

  摘要：

  The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1 mu M. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.01.011

文献信息

• Mutations in the Pseudomonas aeruginosa Needle Protein Gene <i>pscF</i> Confer Resistance to Phenoxyacetamide Inhibitors of the Type III Secretion System
  作者：Nicholas O. Bowlin、John D. Williams、Claire A. Knoten、Matthew C. Torhan、Tommy F. Tashjian、Bing Li、Daniel Aiello、Joan Mecsas、Alan R. Hauser、Norton P. Peet、Terry L. Bowlin、Donald T. Moir

  DOI：10.1128/aac.02795-13

  日期：2014.4

  The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structure-activity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF , encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF , together with its chaperone and cochaperone genes pscE and pscG , to a Δ pscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF.

  摘要 III型分泌系统（T3SS）是铜绿假单胞菌中一种临床上重要的毒力机制。 铜绿假单胞菌 Ⅲ型分泌系统（T3SS）是铜绿假单胞菌的一种重要临床毒力机制，它能将效应毒素分泌并转运到宿主细胞中，从而阻碍宿主对感染做出快速的先天免疫反应。T3SS 抑制剂可作为预防或辅助治疗药物，增强抗生素在铜绿假单胞菌感染中的活性。 铜绿假单胞菌 感染（如肺炎和菌血症）的抗生素活性。其中一种抑制剂是苯氧乙酰胺 MBX 1641，它对铜绿假单胞菌的抑制表现出非常灵敏的结构-活性关系，包括显著的立体选择性。 铜绿假单胞菌 T3SS。这些特征表明它与一个特定但未知的蛋白质靶点相互作用。在这里，我们通过分离抑制剂抗性突变体并通过深度测序绘制突变位点图，确定了明显的分子靶标。对四个对苯氧乙酰胺抑制剂 MBX 2359 具有抗性的独立突变体进行筛选和测序，确定了 T3SS 基因 pscF 是所有四个菌株唯一共同的突变位点。将野生型和突变等位基因的 的野生型和突变等位基因 及其伴侣蛋白和辅助伴侣蛋白基因 pscE 和 基因 转变为 Δ pscF 铜绿微囊藻 菌株中的每个单密码子突变都证明了 单密码子突变 中的每个单密码子突变对提供分泌和转运是必要且足够的，这些分泌和转运对多种苯氧乙酰胺抑制剂类似物具有抗性，但对具有不同化学支架的 T3SS 抑制剂没有抗性。这些结果表明，PscF 针蛋白显然是发现 T3SS 抑制剂的一个新分子靶点，并表明其他三种化学性质不同的 T3SS 抑制剂与 PscF 的一个或多个不同靶点或不同区域相互作用。
• INHIBITORS OF BACTERIAL TYPE III SECRETION SYSTEM
  申请人：Moir Donald T.

  公开号：US20140219995A1

  公开（公告）日：2014-08-07

  Organic compounds showing the ability to inhibit effector toxin secretion or translocation mediated by bacterial type III secretion systems are disclosed. The disclosed type III secretion system inhibitor compounds are useful for combating infections by Gram-negative bacteria such as Salmonella spp., Shigella flexneri, Pseudomonas spp., Yersinia spp., enteropathogenic and enteroinvasive Escherichia coli , and Chlamydia spp. having such type III secretion systems.

  本发明揭示了一种有机化合物，其具有抑制由细菌III型分泌系统介导的效应毒素分泌或转位的能力。揭示的III型分泌系统抑制剂化合物对于对抗革兰氏阴性菌的感染非常有用，例如沙门氏菌属，弯曲杆菌，假单胞菌属，耶尔森菌属，肠致病性和肠侵袭性大肠杆菌以及具有此类III型分泌系统的沙眼衣原体属。
• [EN] INHIBITORS OF BACTERIAL TYPE III SECRETION SYSTEM<br/>[FR] INHIBITEURS DU SYSTÈME DE SÉCRÉTION BACTÉRIENNE DE TYPE III
  申请人：MICROBIOTIX INC

  公开号：WO2013010089A2

  公开（公告）日：2013-01-17

  Organic compounds showing the ability to inhibit effector toxin secretion or translocation mediated by bacterial type III secretion systems are disclosed. The disclosed type III secretion system inhibitor compounds are useful for combating infections by Gram-negative bacteria such as Salmonella spp., Shigella flexneri, Pseudomonas spp., Yersinia spp., enteropathogenic and enteroinvasive Escherichia coli, and Chlamydia spp. having such type III secretion systems.
• Synthesis and structure–activity relationships of novel phenoxyacetamide inhibitors of the Pseudomonas aeruginosa type III secretion system (T3SS)
  作者：John D. Williams、Matthew C. Torhan、Venugopal R. Neelagiri、Carson Brown、Nicholas O. Bowlin、Ming Di、Courtney T. McCarthy、Daniel Aiello、Norton P. Peet、Terry L. Bowlin、Donald T. Moir

  DOI：10.1016/j.bmc.2015.01.011

  日期：2015.3

  The increasing prevalence of drug-resistant bacterial infections is driving the discovery and development not only of new antibiotics, but also of inhibitors of virulence factors that are crucial for in vivo pathogenicity. One such virulence factor is the type III secretion system (T3SS), which plays a critical role in the establishment and dissemination of Pseudomonas aeruginosa infections. We have recently described the discovery and characterization of a series of inhibitors of P. aeruginosa T3SS based on a phenoxyacetamide scaffold. To better characterize the factors involved in potent T3SS inhibition, we have conducted a systematic exploration of this structure, revealing several highly responsive structure-activity relationships indicative of interaction with a specific target. Most of the structural features contributing to potency were additive, and combination of those features produced optimized inhibitors with IC50 values <1 mu M. (C) 2015 Elsevier Ltd. All rights reserved.