N-(1-benzofuran-2-ylcarbonyl)-L-phenylalanine | 1446027-52-6

• 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-(1-benzofuran-2-ylcarbonyl)-L-phenylalanine
• 英文别名: (2S)-2-(1-benzofuran-2-carbonylamino)-3-phenylpropanoic acid
• CAS: 1446027-52-6
• 化学式: C₁₈H₁₅NO₄
• 分子量: 309.321
• InChiKey: JUPWRZINZQTDCI-AWEZNQCLSA-N

物化性质

• 沸点：
  583.1±45.0 °C(Predicted)
• 密度：
  1.313±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  79.5
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(1-benzofuran-2-ylcarbonyl)-L-phenylalanine 在 sodium tetrahydroborate 、 碳酸氢钠 、 戴斯-马丁氧化剂 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 9.5h， 生成 N-((S)-1-oxo-1-(((S)-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)amino)-3-phenylpropan-2-yl)benzofuran-2-carboxamide
  参考文献：
  名称：

  α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

  摘要：

  The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclo-hexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

  DOI：

  10.1021/acs.jmedchem.9b01828
• 作为产物：
  描述：

  1-苯并呋喃-2-羰酰氯 在 水 、 三乙胺 、 sodium hydroxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 2.33h， 生成 N-(1-benzofuran-2-ylcarbonyl)-L-phenylalanine
  参考文献：
  名称：

  α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment

  摘要：

  The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclo-hexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.

  DOI：

  10.1021/acs.jmedchem.9b01828

文献信息

• NOVEL 4-SUBSTITUTED-3-PEPTIDYL-AZETIDIN-2-ONE DERIVATIVES USEFUL AS CYSTEINE PROTEINASE INHIBITOR
  申请人：SYNPHAR LABORATORIES INC.

  公开号：EP0817795A1

  公开（公告）日：1998-01-14
• US5986108A
  申请人：——

  公开号：US5986108A

  公开（公告）日：1999-11-16
• [EN] NOVEL 4-SUBSTITUTED-3-PEPTIDYL-AZETIDIN-2-ONE DERIVATIVES USEFUL AS CYSTEINE PROTEINASE INHIBITOR<br/>[FR] NOUVEAUX DERIVES 3-PEPTIDYL-AZETIDIN-2-ONE SUBSTITUEE EN 4 UTILES EN TANT QU'INHIBITEUR DES CYSTEINES PROTEINASES
  申请人：SYNPHAR LABORATORIES, INC.

  公开号：WO1996032408A1

  公开（公告）日：1996-10-17

  (EN) Certain 4-substituted-3-peptidyl-azetidin-2-one compounds exhibit excellent cysteine proteinase inhibitory activity which can be used in the treatment of different diseases such as muscular dystrophy, bone resorption, myocardial infarction and cancer metastasis. These compounds are 4-substituted-3-peptidyl-azetidin-2-ones of formula (I) or pharmaceutically acceptable salts thereof, wherein R1 is hydrogen; C1-C6 alkyl which is unsubstituted or substituted; R2 is selected from the group consisting of hydrogen; C1-C6 alkyl which is unsubstituted or substituted; -XR6 wherein X is O, S, SO, or SO2; R6 is C1-C6 alkyl which is unsubstituted or substituted. Peptidyl group is a 1-2 amino acid residue wherein the free NH2 is unsubstituted or substituted with a protective group selected from the group consisting of aryloxy carbonyl, alkoxy carbonyl, substituted alkanoyl, arylalkanoyl, arylalkenoyl, heterocyclealkanoyl, heterocyclealkenoyl alkylsulphonyl, arylsulphonyl, arylalkanylsulphonyl, arylalkensulphonyl, heterocyclealkanylsulphonyl, heterocyclealkensulphonyl, and heteroarylsulphonyl.(FR) Certains composés 3-peptidyl-azétidin-2-one substituée en 4 possèdent une excellente activité d'inhibition des cystéines protéinases, et on peut les utiliser dans le traitement de différentes maladies telles que la myopathie primitive progressive, la résorption osseuse, l'infarctus du myocarde et les métastases cancéreuses. Ces composés sont des 3-peptidyl-azétidin-2-ones substituées en 4 de la formule (I), ou des sels de celles-ci, acceptables sur le plan pharmacologique. Dans cette formule, R1 représente hydrogène, alkyle C1-C6 substitué ou non; R2 est choisi dans le groupe constitué par hydrogène, alkyle C1-C6 substitué ou non, -XR6 où X représente O, S, SO ou SO2 et R6 représente alkyle C1-C6 substitué ou non. Le groupe peptidyle est un reste d'acide aminé 1-2 dans lequel le groupe libre NH2 n'est pas substitué ou l'est par un groupe protecteur choisi dans le groupe constitué par aryloxy carbonyle, alcoxy carbonyle, alcanoyle substitué, arylalcanoyle, arylalcénoyle, hétérocycle-alcanoyle, hétérocyle-alcénoyle, alkylsulphonyle, arylsulphonyle, arylalcanylsulphonyle, arylalcènesulphonyle, hétérocycle-alcanylsulphonyle, hétérocycle-alcènesulphonyle et hétéroarylsulphonyle.
• α-Ketoamides as Broad-Spectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-Based Design, Synthesis, and Activity Assessment
  作者：Linlin Zhang、Daizong Lin、Yuri Kusov、Yong Nian、Qingjun Ma、Jiang Wang、Albrecht von Brunn、Pieter Leyssen、Kristina Lanko、Johan Neyts、Adriaan de Wilde、Eric J. Snijder、Hong Liu、Rolf Hilgenfeld

  DOI：10.1021/acs.jmedchem.9b01828

  日期：2020.5.14

  The main protease of coronaviruses and the 3C protease of enteroviruses share a similar active-site architecture and a unique requirement for glutamine in the P1 position of the substrate. Because of their unique specificity and essential role in viral polyprotein processing, these proteases are suitable targets for the development of antiviral drugs. In order to obtain near-equipotent, broad-spectrum antivirals against alphacoronaviruses, betacoronaviruses, and enteroviruses, we pursued a structure-based design of peptidomimetic alpha-ketoamides as inhibitors of main and 3C proteases. Six crystal structures of protease-inhibitor complexes were determined as part of this study. Compounds synthesized were tested against the recombinant proteases as well as in viral replicons and virus-infected cell cultures; most of them were not cell-toxic. Optimization of the P2 substituent of the alpha-ketoamides proved crucial for achieving near-equipotency against the three virus genera. The best near-equipotent inhibitors, 11u (P2 = cyclopentylmethyl) and 11r (P2 = cyclo-hexylmethyl), display low-micromolar EC50 values against enteroviruses, alphacoronaviruses, and betacoronaviruses in cell cultures. In Huh7 cells, 11r exhibits three-digit picomolar activity against the Middle East Respiratory Syndrome coronavirus.