(R)-N-((1S,2R)-2-hydroxy-1-indanyl)-5,5-dimethylthiazolidine-4-carboxamide | 819083-86-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (R)-N-((1S,2R)-2-hydroxy-1-indanyl)-5,5-dimethylthiazolidine-4-carboxamide
• CAS: 819083-86-8
• 化学式: C₁₅H₂₀N₂O₂S
• 分子量: 292.402
• InChiKey: MQIASATUWYCNEY-FRRDWIJNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  20.0
• 可旋转键数：
  2.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  61.36
• 氢给体数：
  3.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (R)-N-((1S,2R)-2-hydroxy-1-indanyl)-5,5-dimethylthiazolidine-4-carboxamide 在 盐酸 、 1-羟基苯并三唑 、 苯甲醚 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 生成 (R)-3-((2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl)-N-((1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl)-5,5-dimethylthiazolidine-4-carboxamide
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052
• 作为产物：
  描述：

  (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-tert-butoxycarbonyl-5,5-dimethyl-1,3-thiazolidine-4-carboxamide 在 盐酸 、 苯甲醚 作用下， 以 1,4-二氧六环 为溶剂， 生成 (R)-N-((1S,2R)-2-hydroxy-1-indanyl)-5,5-dimethylthiazolidine-4-carboxamide
  参考文献：
  名称：

  Additional interaction of allophenylnorstatine-containing tripeptidomimetics with malarial aspartic protease plasmepsin II

  摘要：

  Based on a highly potent allophenylnorstatine-containing inhibitor, KNI-10006, against the plasmepsins of Plasmodium falciparum, we synthesized a series of tripeptide-type compounds with various N-terminal moieties and evaluated their inhibitory activities against plasmepsin II. Certain phenylacetyl derivatives exhibited extremely high affinity with Ki values of less than 0.1 nM suggesting successful hydrophobic interactions. (C) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.03.052

文献信息

• α-Substituted norstatines as the transition-state mimic in inhibitors of multiple digestive vacuole malaria aspartic proteases
  作者：Kristina M. Orrling、Melissa R. Marzahn、Hugo Gutiérrez-de-Terán、Johan Åqvist、Ben M. Dunn、Mats Larhed

  DOI：10.1016/j.bmc.2009.06.065

  日期：2009.8

  compounds provided Ki values in the nanomolar range for all PM4, with a best value of 110 nM in PM4 from Plasmodium ovale. In addition, excellent selectivity over the closely related human aspartic protease Cathepsin D was achieved. The loss of affinity to Plasmodium falciparum PM4, which was experienced upon the move of the P1 substituent, was rationalized by the calculation of inhibitor–protein binding

  研究了含降nor素的纤溶酶抑制剂中P1侧链从β位置移动到α位置的影响，产生了两类新的含叔醇的α-苄基去甲他汀和α-苯基去甲他汀。设计，合成和评估了十二种α-取代的诺他汀类药物对所有四种导致人类疟疾的疟原虫的消化液中存在的纤溶酶II和纤溶酶IV直向同源物（PM4）的抑制作用。已开发出新的合成路线来生产所需的α-取代的诺他汀类药物，为纯立体异构体。最好的化合物为所有PM4提供的K i值都在纳摩尔范围内，椭圆疟原虫的PM4的最佳值为110 nM。另外，获得了与密切相关的人天冬氨酸蛋白酶组织蛋白酶D的优异的选择性。通过使用线性相互作用能法（LIE）计算抑制剂与蛋白质的结合亲和力，可以合理化丧失P1取代基后对恶性疟原虫PM4的亲和力。
• How Much Binding Affinity Can be Gained by Filling a Cavity?
  作者：Yuko Kawasaki、Eduardo E. Chufan、Virginie Lafont、Koushi Hidaka、Yoshiaki Kiso、L. Mario Amzel、Ernesto Freire

  DOI：10.1111/j.1747-0285.2009.00921.x

  日期：2010.2

  Binding affinity optimization is critical during drug development. Here, we evaluate the thermodynamic consequences of filling a binding cavity with functionalities of increasing van der Waals radii (–H, –F, –Cl, and CH3) that improve the geometric fit without participating in hydrogen bonding or other specific interactions. We observe a binding affinity increase of two orders of magnitude. There appears to be three phases in the process. The first phase is associated with the formation of stable van der Waals interactions. This phase is characterized by a gain in binding enthalpy and a loss in binding entropy, attributed to a loss of conformational degrees of freedom. For the specific case presented in this article, the enthalpy gain amounts to −1.5 kcal/mol while the entropic losses amount to +0.9 kcal/mol resulting in a net 3.5‐fold affinity gain. The second phase is characterized by simultaneous enthalpic and entropic gains. This phase improves the binding affinity 25‐fold. The third phase represents the collapse of the trend and is triggered by the introduction of chemical functionalities larger than the binding cavity itself [CH(CH3)2]. It is characterized by large enthalpy and affinity losses. The thermodynamic signatures associated with each phase provide guidelines for lead optimization.