5-(benzimidazol-1-yl)-N-cyclobutylthiophene-2-carboxamide | 1195774-29-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5-(benzimidazol-1-yl)-N-cyclobutylthiophene-2-carboxamide
• CAS: 1195774-29-8
• 化学式: C₁₆H₁₅N₃OS
• 分子量: 297.381
• InChiKey: WREVZKANZSJFPC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  75.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-溴-2-羧基噻吩 在 N-甲基吗啉 、 copper(I) oxide 、 1-羟基苯并三唑 、 caesium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 2-氨基-4,6-二羟基嘧啶 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 为溶剂， 反应 13.0h， 生成 5-(benzimidazol-1-yl)-N-cyclobutylthiophene-2-carboxamide
  参考文献：
  名称：

  Optimization of Potent Inhibitors of P. falciparum Dihydroorotate Dehydrogenase for the Treatment of Malaria

  摘要：

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.

  DOI：

  10.1021/ml200143c

文献信息

• SMALL MOLECULE INHIBITORS OF PLASMODIUM FALCIPARUM DIHYDROOROTATE DEHYDROGENASE
  申请人：Bastos Cecilia

  公开号：US20110130381A1

  公开（公告）日：2011-06-02

  Inhibitors of dihydroorotate dehydrogenase (DHODH) for the Plasmodium enzyme have been identified and characterized. The inhibitors have high specificity, submicromolar efficacy against cultured parasite strains, exhibit drug-like properties, and are not overtly cytotoxic.

  已经鉴定和表征了针对疟原虫酶的脱氢脱氧尿嘧啶酸脱氢酶（DHODH）抑制剂。这些抑制剂具有高度特异性，在培养的寄生虫株中具有亚微摩尔效力，具有类似药物的特性，并且不明显细胞毒性。
• US8703811B2
  申请人：——

  公开号：US8703811B2

  公开（公告）日：2014-04-22
• [EN] SMALL MOLECULE INHIBITORS OF PLASMODIUM FALCIPARUM DIHYDROOROTATE DEHYDROGENASE<br/>[FR] INHIBITEURS À PETITES MOLÉCULES DE DIHYDROOROTATE DÉSHYDROGÉNASE DE PLASMODIUM FALCIPARUM
  申请人：MASSACHUSETTS INST TECHNOLOGY

  公开号：WO2009137081A2

  公开（公告）日：2009-11-12

  Inhibitors of dihydroorotate dehydrogenase (DHODH) for the Plasmodium enzyme have been identified and characterized. The inhibitors have high specificity, submicromolar efficacy against cultured parasite strains, exhibit drug-like properties, and are not overtly cytotoxic.
• Optimization of Potent Inhibitors of <i>P. falciparum</i> Dihydroorotate Dehydrogenase for the Treatment of Malaria
  作者：Renato T. Skerlj、Cecilia M. Bastos、Michael L. Booker、Martin L. Kramer、Robert H. Barker、Cassandra A. Celatka、Thomas J. O’Shea、Benito Munoz、Amar Bir Sidhu、Joseph F. Cortese、Sergio Wittlin、Petros Papastogiannidis、Inigo Angulo-Barturen、Maria Belen Jimenez-Diaz、Edmund Sybertz

  DOI：10.1021/ml200143c

  日期：2011.9.8

  Inhibition of dihydroorotate dehydrogenase (DHODH) for P. falciparum potentially represents a new treatment option for malaria, since DHODH catalyzes the rate-limiting step in the pyrimidine biosynthetic pathway and P. falciparum is unable to salvage pyrimidines and must rely on de novo biosynthesis for survival. We report herein the synthesis and structure-activity relationship of a series of 5-(2-methylbenzimidazol-1-yl)-N-alkylthiophene-2-carboxamides that are potent inhibitors against PfDHODH but do not inhibit the human enzyme. On the basis of efficacy observed in three mouse models of malaria, acceptable safety pharmacology risk assessment and safety toxicology profile in rodents, lack of potential drug-drug interactions, acceptable ADME/pharmacokinetic profile, and projected human dose, 5-(4-cyano-2-methyl-1H-benzo[d]imidazol-1-yl)-N-cyclopropylthiophene-2-carboxamide 2q was identified as a potential drug development candidate.