N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-(4-tolyloxy)acetamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-(4-tolyloxy)acetamide
• 英文别名: 2-(4-methylphenoxy)-N-(1-oxo-3H-2-benzofuran-5-yl)acetamide
• 化学式: C₁₇H₁₅NO₄
• 分子量: 297.31
• InChiKey: LFJPXYSLCHLSFJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-氨基苯酞 在 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 生成  N-(1-oxo-1,3-dihydroisobenzofuran-5-yl)-2-(4-tolyloxy)acetamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of Helicobacter pylori inosine 5′-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2

  摘要：

  Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDH5, microbial IMPDH5 are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated >= 70% HpIMPDH inhibition at 10 mu M concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 mu M) in the series. The study reaffirmed the utility of 5-aminoisobenzofiffan-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.

  DOI：

  10.1016/j.bioorg.2019.04.001

文献信息

• Design, synthesis and biological evaluation of Helicobacter pylori inosine 5′-monophosphate dehydrogenase (HpIMPDH) inhibitors. Further optimization of selectivity towards HpIMPDH over human IMPDH2
  作者：Chetan P. Shah、Gayathri Purushothaman、Vijay Thiruvenkatam、Sivapriya Kirubakaran、Kapil Juvale、Prashant S. Kharkar

  DOI：10.1016/j.bioorg.2019.04.001

  日期：2019.6

  Inosine 5'-monophosphate dehydrogenase (IMPDH, EC 1.1.1.205) catalyzes a crucial step in guanine nucleotide biosynthesis, thereby governing cell proliferation. In contrast to mammalian IMPDH5, microbial IMPDH5 are relatively less explored as potential targets for antimicrobial drug discovery. In continuation with our previous work, here we report the discovery of moderately potent and highly selective Helicobacter pylori IMPDH (HpIMPDH) inhibitors. The present study is mainly focused around our previously identified, modestly potent and relatively nonselective (for HpIMPDH over human IMPDH2) hit molecule IX (16i). In an attempt to optimize the selectivity for the bacterial enzyme, we screened a set of 48 redesigned new chemical entities (NCEs) belonging to 5-aminoisobenzofuran-1(3H)-one series for their in vitro HpIMPDH and human IMPDH2 inhibition. A total of 12 compounds (hits) demonstrated >= 70% HpIMPDH inhibition at 10 mu M concentration; none of the hits were active against hIMPDH2. Compound 24 was found to be the most potent and selective molecule (HpIMPDH IC50 = 2.21 mu M) in the series. The study reaffirmed the utility of 5-aminoisobenzofiffan-1(3H)-one as a promising scaffold with great potential for further development of potent and selective HpIMPDH inhibitors.