(R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide hydrochloride | 1093076-74-4

• 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: (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide hydrochloride
• CAS: 1093076-74-4
• 化学式: C₂₅H₃₁N₃O₄S*ClH
• 分子量: 506.066
• InChiKey: VAEUJNSECQYAAQ-XLGQSWBBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.79
• 重原子数：
  34.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  115.89
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide hydrochloride 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
  参考文献：
  名称：

  Identification of Highly Potent Human Immunodeficiency Virus Type-1 Protease Inhibitors against Lopinavir and Darunavir Resistant Viruses from Allophenylnorstatine-Based Peptidomimetics with P2 Tetrahydrofuranylglycine

  摘要：

  The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P-3, P-2, and P-2' moieties. The derivatives with P-2 tetrahydrofur-anylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.

  DOI：

  10.1021/acs.jmedchem.7b01709
• 作为产物：
  描述：

  (R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-(tert-butoxycarbonyl)amino-2-hydroxy-4-phenylbutanoyl]-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， 反应 1.5h， 以12.34 g的产率得到(R)-N-[(1S,2R)-2-hydroxyindan-1-yl]-3-[(2S,3S)-3-amino-2-hydroxy-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide hydrochloride
  参考文献：
  名称：

  在抗疟疾活动增强羟甲基羰基（HMC）基于等位基因的二肽模拟物，针对疟疾天冬氨酸蛋白酶的组织蛋白酶。

  摘要：

  纤溶酶（Plm）是新型抗疟药的潜在靶标，但是大多数报道的Plm抑制剂具有相对较低的抗疟活性。我们合成了一系列的二肽型HIV蛋白酶抑制剂，其中含有一个别苯基去甲他汀-二甲基硫代脯氨酸支架，以表现出对Plm II的有效抑制活性。在感染的红细胞分析中，它们对恶性疟原虫的活性与针对靶酶的活性有很大不同。为了提高拟肽Plm抑制剂的抗疟疾活性，我们在高效Plm抑制剂KNI-10006的结构上连接了取代基。在这些衍生物中，我们确定了烷基氨基化合物，例如44（KNI-10283）和47（KNI-10538），其抗疟活性提高了15倍以上，达到亚微摩尔水平，保持其强大的Plm II抑制活性和低细胞毒性。这些结果表明，特定碱性基团上的辅助取代基有助于将抑制剂递送至靶标Plm。

  DOI：

  10.1016/j.bmc.2008.10.011

文献信息

• Small-Sized Human Immunodeficiency Virus Type-1 Protease Inhibitors Containing Allophenylnorstatine to Explore the S₂′ Pocket
  作者：Koushi Hidaka、Tooru Kimura、Hamdy M. Abdel-Rahman、Jeffrey-Tri Nguyen、Keith F. McDaniel、William E. Kohlbrenner、Akhteruzzaman Molla、Motoyasu Adachi、Taro Tamada、Ryota Kuroki、Noriko Katsuki、Yoshiaki Tanaka、Hikaru Matsumoto、Jun Wang、Yoshio Hayashi、Dale J. Kempf、Yoshiaki Kiso

  DOI：10.1021/jm9005115

  日期：2009.12.10

  A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P-2' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate I (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of all anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity, X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group kit P-2' position revealed hydrophobic interactions with Ala28, Ile84, kind Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.
• Improvement of both plasmepsin inhibitory activity and antimalarial activity by 2-aminoethylamino substitution
  作者：Takuya Miura、Koushi Hidaka、Tsuyoshi Uemura、Keisuke Kashimoto、Yuto Hori、Yuko Kawasaki、Adam J. Ruben、Ernesto Freire、Tooru Kimura、Yoshiaki Kiso

  DOI：10.1016/j.bmcl.2010.06.099

  日期：2010.8

  We attached 2-aminoethylamino groups to allophenylnorstatine-containing plasmepsin (Plm) inhibitors and investigated SAR of the methyl or ethyl substitutions on the amino groups. Unexpectedly, compounds 22 (KNI-10743) and 25 (KNI-10742) exhibited extremely potent Plm II inhibitory activities (K-i < 0.1 nM). Moreover, among our peptidomimetic Plm inhibitors, we identified the compounds with the highest antimalarial activity using a SYBR Green I-based fluorescence assay. (C) 2010 Elsevier Ltd. All rights reserved.