N-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-4,5-dimethoxy-2-nitrobenzamide

• 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: N-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-4,5-dimethoxy-2-nitrobenzamide
• 化学式: C₁₇H₂₀N₄O₅S
• mdl: MFCD03616227
• 分子量: 392.436
• InChiKey: RFPXEPMAFLDHQZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  147
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  5-环己基-1,3,4-噻二唑-2-胺 、 6-硝基藜芦酸 在 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以57%的产率得到N-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-4,5-dimethoxy-2-nitrobenzamide
  参考文献：
  名称：

  Lipoprotein Signal Peptidase Inhibitors with Antibiotic Properties Identified through Design of a Robust In Vitro HT Platform

  摘要：

  As resistance to antibiotics increases, the exploration of new targets and strategies to combat pathogenic bacteria becomes more urgent. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host, and have robust assays to quantitate activity and identify inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and comprehensively fits these criteria. Here, we have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp. We employed our high-throughput screen assay against 646,275 compounds to discover inhibitors of Lsp and synthesized a range of analogs to generate molecules with nanomolar half maximal inhibitory concentration values. Importantly, our inhibitors are effective in preventing the growth of E. coli cultures in the presence of outermembrane permeabilizer PMBN and should facilitate development of antibacterial agents with a novel mechanism of action to treat antibiotic-resistant bacteria.

  DOI：

  10.1016/j.chembiol.2017.12.011

文献信息

• [EN] BENZAMIDE INHIBITORS OF BACTERICAL LIPOPROTEIN SIGNAL PEPTIDASE<br/>[FR] INHIBITEURS DE TYPE BENZAMIDE DE LA PEPTIDASE DU PEPTIDE SIGNAL DES LIPOPROTÉINES BACTÉRIENNES
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2019010165A1

  公开（公告）日：2019-01-10

  Increasing resistance to antibiotics necessitates discovery of new targets and strategies to combat bacteria. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host and have robust assays to quantitate activity and identify novel inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and entirely fits these criteria. We have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp. We employed our HTS assay against 646,275 compounds to discover inhibitors of Lsp and synthesized a range of analogues to generate molecules with nanomolar IC50 values. Importantly, our inhibitors are effective in preventing the growth of E. coli cultures. Our Lsp assay will be a useful tool for biologists to monitor Lsp activity and our inhibitors will facilitate development of antibacterial agents to potentially treat antibiotic-resistant bacteria.

  抗生素的抗性增加使得必须发现新的靶点和策略来对抗细菌。理想的蛋白靶点需要在许多物种中具有生存能力，对原核生物独特，以限制对宿主的影响，并且具有强大的测定活性和识别新型抑制剂的方法。脂蛋白信号肽酶（Lsp）是一种跨膜天冬氨酸蛋白酶，用于脂蛋白成熟，完全符合这些标准。我们开发了第一个体外高通量测定来监测Lsp的蛋白水解作用。我们使用我们的高通量筛选测定对646,275种化合物进行了筛选，以发现Lsp的抑制剂，并合成了一系列类似物，生成具有纳摩尔IC50值的分子。重要的是，我们的抑制剂能够有效地阻止大肠杆菌培养物的生长。我们的Lsp测定将成为生物学家监测Lsp活性的有用工具，我们的抑制剂将有助于开发抗菌剂，可能用于治疗抗生素耐药细菌。
• BENZAMIDE INHIBITORS OF BACTERIAL LIPOPROTEIN SIGNAL PEPTIDASE
  申请人：The Scripps Research Institute

  公开号：US20200181101A1

  公开（公告）日：2020-06-11

  Increasing resistance to antibiotics necessitates discovery of new targets and strategies to combat bacteria. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host and have robust assays to quantitate activity and identify novel inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and entirely fits these criteria. We have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp. We employed our HTS assay against 646,275 compounds to discover inhibitors of Lsp and synthesized a range of analogues to generate molecules with nanomolar IC50 values. Importantly, our inhibitors are effective in preventing the growth of E. coli cultures. Our Lsp assay will be a useful tool for biologists to monitor Lsp activity and our inhibitors will facilitate development of antibacterial agents to potentially treat antibiotic-resistant bacteria.
• Lipoprotein Signal Peptidase Inhibitors with Antibiotic Properties Identified through Design of a Robust In Vitro HT Platform
  作者：Seiya Kitamura、Anna Owensby、Daniel Wall、Dennis W. Wolan

  DOI：10.1016/j.chembiol.2017.12.011

  日期：2018.3

  As resistance to antibiotics increases, the exploration of new targets and strategies to combat pathogenic bacteria becomes more urgent. Ideal protein targets are required for viability across many species, are unique to prokaryotes to limit effects on the host, and have robust assays to quantitate activity and identify inhibitors. Lipoprotein signal peptidase (Lsp) is a transmembrane aspartyl protease required for lipoprotein maturation and comprehensively fits these criteria. Here, we have developed the first in vitro high-throughput assay to monitor proteolysis by Lsp. We employed our high-throughput screen assay against 646,275 compounds to discover inhibitors of Lsp and synthesized a range of analogs to generate molecules with nanomolar half maximal inhibitory concentration values. Importantly, our inhibitors are effective in preventing the growth of E. coli cultures in the presence of outermembrane permeabilizer PMBN and should facilitate development of antibacterial agents with a novel mechanism of action to treat antibiotic-resistant bacteria.