4-(1-(2-cyclopropyl-2-oxoethyl)-4-methyl-2,5-dioxoimidazolidin-4-yl)benzenesulfonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 4-(1-(2-cyclopropyl-2-oxoethyl)-4-methyl-2,5-dioxoimidazolidin-4-yl)benzenesulfonamide
• 英文别名: 4-[1-(2-Cyclopropyl-2-oxoethyl)-4-methyl-2,5-dioxoimidazolidin-4-yl]benzenesulfonamide；4-[1-(2-cyclopropyl-2-oxoethyl)-4-methyl-2,5-dioxoimidazolidin-4-yl]benzenesulfonamide
• 化学式: C₁₅H₁₇N₃O₅S
• 分子量: 351.383
• InChiKey: CZQPOADORFDROM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-乙酰基苯磺酰胺 在 potassium carbonate 作用下， 以 乙醇 、 水 为溶剂， 生成 4-(1-(2-cyclopropyl-2-oxoethyl)-4-methyl-2,5-dioxoimidazolidin-4-yl)benzenesulfonamide
  参考文献：
  名称：

  Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β-d-Ribose Oxidase (DprE1) Inhibitors

  摘要：

  In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-beta-D-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.

  DOI：

  10.1021/acs.jmedchem.0c00107

文献信息

• Optimization of Hydantoins as Potent Antimycobacterial Decaprenylphosphoryl-β-<scp>d</scp>-Ribose Oxidase (DprE1) Inhibitors
  作者：Olga Balabon、Eleni Pitta、Maciej K. Rogacki、Eugenia Meiler、Ruth Casanueva、Laura Guijarro、Sophie Huss、Eva Maria Lopez-Roman、Ángel Santos-Villarejo、Koen Augustyns、Lluis Ballell、David Barros Aguirre、Robert H. Bates、Fraser Cunningham、Monica Cacho、Pieter Van der Veken

  DOI：10.1021/acs.jmedchem.0c00107

  日期：2020.5.28

  In search of novel drugs against tuberculosis, we previously discovered and profiled a novel hydantoin-based family that demonstrated highly promising in vitro potency against Mycobacterium. tuberculosis. The compounds were found to be noncovalent inhibitors of DprE1, a subunit of decaprenylphosphoryl-beta-D-ribose-2'-epimerase. This protein, localized in the periplasmic space of the mycobacterial cell wall, was shown to be an essential and vulnerable antimycobacterial drug target. Here, we report the further SAR exploration of this chemical family through more than 80 new analogues. Among these, the most active representatives combined submicromolar cellular potency and nanomolar target affinity with balanced physicochemical properties and low human cytotoxicity. Moreover, we demonstrate in vivo activity in an acute Mtb infection model and provide further proof of DprE1 being the target of the hydantoins. Overall, the hydantoin family of DprE1 inhibitors represents a promising noncovalent lead series for the discovery of novel antituberculosis agents.