tert-butyl N-[2-[[6-[[benzyl-[[3-(trifluoromethyl)phenyl]methyl]amino]methyl]pyridin-2-yl]methyl-[(3-methylphenyl)methyl]amino]ethyl]-N-(3-hydroxypropyl)carbamate | 204196-33-8

• 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: tert-butyl N-[2-[[6-[[benzyl-[[3-(trifluoromethyl)phenyl]methyl]amino]methyl]pyridin-2-yl]methyl-[(3-methylphenyl)methyl]amino]ethyl]-N-(3-hydroxypropyl)carbamate
• CAS: 204196-33-8
• 化学式: C₄₀H₄₉F₃N₄O₃
• 分子量: 690.849
• InChiKey: XYGGCEGPQLOUTG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  50
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  69.1
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[2-[[6-[[benzyl-[[3-(trifluoromethyl)phenyl]methyl]amino]methyl]pyridin-2-yl]methyl-[(3-methylphenyl)methyl]amino]ethyl]-N-(3-hydroxypropyl)carbamate 在 三氟乙酸 作用下， 以 氯仿 为溶剂， 反应 4.0h， 以75%的产率得到3-[2-[[6-[[Benzyl-[[3-(trifluoromethyl)phenyl]methyl]amino]methyl]-2-pyridyl]methyl-(m-tolylmethyl)amino]ethylamino]propan-1-ol
  参考文献：
  名称：

  Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity:  Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry

  摘要：

  A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp(-) and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round actives. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 mu M against S. pyogenes and E. coli imp(-). Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria, Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 mu M, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were >100 mu M. These eight compounds were not active (>100 mu M) against fungus C. albicans.

  DOI：

  10.1021/jm970598u
• 作为产物：
  描述：

  3-甲基苄溴 在 potassium carbonate 、 苯硫酚 、 三乙胺 、 肼 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 7.0h， 生成 tert-butyl N-[2-[[6-[[benzyl-[[3-(trifluoromethyl)phenyl]methyl]amino]methyl]pyridin-2-yl]methyl-[(3-methylphenyl)methyl]amino]ethyl]-N-(3-hydroxypropyl)carbamate
  参考文献：
  名称：

  Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity:  Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry

  摘要：

  A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp(-) and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round actives. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 mu M against S. pyogenes and E. coli imp(-). Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria, Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 mu M, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were >100 mu M. These eight compounds were not active (>100 mu M) against fungus C. albicans.

  DOI：

  10.1021/jm970598u

文献信息

• Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity:  Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry
  作者：Haoyun An、Becky D. Haly、P. Dan Cook

  DOI：10.1021/jm970598u

  日期：1998.2.1

  A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp(-) and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round actives. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 mu M against S. pyogenes and E. coli imp(-). Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria, Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 mu M, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were >100 mu M. These eight compounds were not active (>100 mu M) against fungus C. albicans.