5-(R)-pyrrolidin-3-yl-3-thiophen-2-yl-1,2,4-oxadiazole | 1286708-61-9

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 5-(R)-pyrrolidin-3-yl-3-thiophen-2-yl-1,2,4-oxadiazole
• 英文别名: 5-[(3R)-pyrrolidin-3-yl]-3-thiophen-2-yl-1,2,4-oxadiazole
• CAS: 1286708-61-9
• 化学式: C₁₀H₁₁N₃OS
• 分子量: 221.283
• InChiKey: VPRKZPMAGRPMCP-SSDOTTSWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  79.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4,4,4-三氟丁酸 、 5-(R)-pyrrolidin-3-yl-3-thiophen-2-yl-1,2,4-oxadiazole 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 生成 4,4,4-trifluoro-1-[(R)-3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)-pyrrolidin-1-yl]-butan-1-one
  参考文献：
  名称：

  Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

  DOI：

  10.1021/jm200076a
• 作为产物：
  描述：

  2-氰基噻吩 在 盐酸 、 盐酸羟胺 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.08h， 生成 5-(R)-pyrrolidin-3-yl-3-thiophen-2-yl-1,2,4-oxadiazole
  参考文献：
  名称：

  Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

  DOI：

  10.1021/jm200076a

文献信息

• FLUORALKYLCARBONYL-OXADIAZOLES
  申请人：Universite de Droit et de la Sante de Lille 2

  公开号：US20140309238A1

  公开（公告）日：2014-10-16

  The present invention relates to compounds of Formula (I), wherein R1 is chosen among the following radicals: (II); (III); (IV), (V), (VI) (VII) and n=1 or 2 and m=1 or 2 with the proviso that m=2 when R1 is (VIII). The present invention also relates to the use thereof as drugs, more particularly in the treatment of mycobacterial infections and more particularly in the treatment of tuberculosis.

  本发明涉及式（I）的化合物，其中R1选自以下基团：（II）、（III）、（IV）、（V）、（VI）、（VII），n=1或2，m=1或2，但当R1为（VIII）时，m=2。本发明还涉及其作为药物的用途，特别是在治疗分枝杆菌感染，尤其是在治疗结核病方面的用途。
• 1, 2, 4 - OXADIAZOLE DERIVATIVES AS ETHR INHIBITORS FOR USE IN THE TREATMENT TUBERCULOSIS
  申请人：Université de Droit et de la Santé de Lille 2

  公开号：EP2771338A2

  公开（公告）日：2014-09-03
• US8962658B2
  申请人：——

  公开号：US8962658B2

  公开（公告）日：2015-02-24
• [EN] COMPOUNDS HAVING AN ETHR INHIBITING ACTIVITY - USE OF SAID COMPOUNDS AS DRUGS - PHARMACEUTICAL COMPOSITION AND PRODUCT CONTAINING SAID COMPOUNDS<br/>[FR] COMPOSÉS PRÉSENTANT UNE ACTIVITÉ D'INHIBITION D'ETHR, UTILISATION DESDITS COMPOSÉS EN TANT QUE MÉDICAMENTS, COMPOSITION PHARMACEUTIQUE ET PRODUIT CONTENANT LESDITS COMPOSÉS
  申请人：UNIV LILLE II DROIT & SANTE

  公开号：WO2013060744A2

  公开（公告）日：2013-05-02

  The present invention relates to compounds of Formula (I), wherein R1 is chosen among the following radicals : (II); (III); (IV), (V), (VI) (VII) and n= 1 or 2 and m=1 or 2 with the proviso that m=2 when R1 is (VIII). The present invention also relates to the use thereof as drugs, more particularly in the treatment of mycobacterial infections and more particularly in the treatment of tuberculosis.