2-methyl-N-(4-(5-((2-methylphenyl)sulfonamido)benzo[d]oxazol-2-yl)phenyl)benzenesulfonamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-methyl-N-(4-(5-((2-methylphenyl)sulfonamido)benzo[d]oxazol-2-yl)phenyl)benzenesulfonamide
• 英文别名: 2-methyl-N-[4-[5-[(2-methylphenyl)sulfonylamino]-1,3-benzoxazol-2-yl]phenyl]benzenesulfonamide
• 化学式: C₂₇H₂₃N₃O₅S₂
• 分子量: 533.629
• InChiKey: NXCWWLTWLQEIKK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  135
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-(4-氨基苯基)-5-氨基苯并恶唑 、 邻甲苯磺酰氯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以53%的产率得到2-methyl-N-(4-(5-((2-methylphenyl)sulfonamido)benzo[d]oxazol-2-yl)phenyl)benzenesulfonamide
  参考文献：
  名称：

  Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness

  摘要：

  Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC50 = 7.9 and 3.1 mu M, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.09.051

文献信息

• Targeting the HSP60/10 chaperonin systems of Trypanosoma brucei as a strategy for treating African sleeping sickness
  作者：Sanofar Abdeen、Nilshad Salim、Najiba Mammadova、Corey M. Summers、Karen Goldsmith-Pestana、Diane McMahon-Pratt、Peter G. Schultz、Arthur L. Horwich、Eli Chapman、Steven M. Johnson

  DOI：10.1016/j.bmcl.2016.09.051

  日期：2016.11

  Trypanosoma brucei are protozoan parasites that cause African sleeping sickness in humans (also known as Human African Trypanosomiasis HAT). Without treatment, T. brucei infections are fatal. There is an urgent need for new therapeutic strategies as current drugs are toxic, have complex treatment regimens, and are becoming less effective owing to rising antibiotic resistance in parasites. We hypothesize that targeting the HSP60/10 chaperonin systems in T. brucei is a viable anti-trypanosomal strategy as parasites rely on these stress response elements for their development and survival. We recently discovered several hundred inhibitors of the prototypical HSP60/10 chaperonin system from Escherichia coli, termed GroEL/ES. One of the most potent GroEL/ES inhibitors we discovered was compound 1. While examining the PubChem database, we found that a related analog, 2e-p, exhibited cytotoxicity to Leishmania major promastigotes, which are trypanosomatids highly related to Trypanosoma brucei. Through initial counter screening, we found that compounds 1 and 2e-p were also cytotoxic to Trypanosoma brucei parasites (EC50 = 7.9 and 3.1 mu M, respectively). These encouraging initial results prompted us to develop a library of inhibitor analogs and examine their anti-parasitic potential in vitro. Of the 49 new chaperonin inhibitors developed, 39% exhibit greater cytotoxicity to T. brucei parasites than parent compound 1. While many analogs exhibit moderate cytotoxicity to human liver and kidney cells, we identified molecular substructures to pursue for further medicinal chemistry optimization to increase the therapeutic windows of this novel class of chaperonin-targeting anti-parasitic candidates. An intriguing finding from this study is that suramin, the first-line drug for treating early stage T. brucei infections, is also a potent inhibitor of GroEL/ES and HSP60/10 chaperonin systems. (C) 2016 Elsevier Ltd. All rights reserved.