首页 | 本学科首页   官方微博 | 高级检索  
     


Optimized POCl3-assisted synthesis of 2-amino-1,3,4-thiadiazole/1,3,4-oxadiazole derivatives as anti-influenza agents
Affiliation:1. College of Chemistry and Pharmaceutical Engineering, Huanghuai University, Zhumadian 463000, China;2. State Key Laboratory of Respiratory Disease, Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China;3. Key Laboratory of Modern Preparation of TCM of Ministry of Education & Research Center of Natural Resources of Chinese Medicinal Materials and Ethnic Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang 330004, China
Abstract:Although recent decades have witnessed the synthesis of 1,3,4-thiadiazoles via phosphorus POCl3-promoted cyclization reaction, simultaneous access to 2-amino-1,3,4-thiadiazole and 2-amino-1,3,4-oxadiazole analogs remains unexpected and elusive. Herein, a detailed regiocontrolled synthesis of 2-amino-1,3,4-thiadiazoles in good to high yields with good regioselectivities from readily available thiosemicarbazides using POCl3 was disclosed. Meantime, to establish a comprehensive structure–activity relationship, 2-amino-1,3,4-oxadiazole derivatives as single regioisomers were prepared via EDCI·HCl-triggered cyclization of the thiosemicarbazide intermediates. The in vitro anti-influenza assays proved that the selected compounds with the pyrazine/pyridine ring exhibited certain inhibitory activities against influenza A virus strains A/HK/68 (H3N2) and A/PR/8/34 (H1N1) in MDCK cells. Among them, N-(adamantan-1-yl)-5-(5-(azepan-1-yl)pyrazin-2-yl)-1,3,4-thiadiazol-2-amine (4j) was the most active compound, and exhibited favorable activity with EC50 values of 3.5 μM and 7.5 μM, respectively. In addition, the molecular docking results explained the reason why compound 4j had dual inhibitory activity and revealed the reasonable binding mode of this compound with the M2-S31N and M2-WT ion channels. This compound had the potential to be further developed as an anti-influenza drug.
Keywords:2-amino-1,3,4-thiadiazole  Dehydrative cyclization  Phosphorus oxychloride  Regioselectivity  Anti-influenza activity  phosphorus oxychloride  EDCI·HCl"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0045"  },"  $$"  :[{"  #name"  :"  text"  ,"  $$"  :[{"  #name"  :"  italic"  ,"  _"  :"  N"  },{"  #name"  :"  __text__"  ,"  _"  :"  -(3-Dimethylaminopropyl)-"  },{"  #name"  :"  italic"  ,"  _"  :"  N′"  },{"  #name"  :"  __text__"  ,"  _"  :"  -ethylcarbodiimide hydrochloride  MDCK"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0055"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  Madin-Darby canine kidney  half maximal effective concentration  50% cytotoxic concentration  SI"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0085"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  Selectivity index  M2"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0095"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  matrix-2 protein  S31N"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0105"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  Serine 31 arganine  WT"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0115"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  wild type  p-Toluenesulfonyl chloride  TEA"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0135"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  triethylamine  DDQ"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0145"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  2,3-dichloro-5,6-dicyano-1,4-benzoquinone  HMA"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0155"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  hexamethylene amiloride  CPE"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0165"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  cytopathic effect  MTT"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0175"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide  AMD"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0185"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  Amantadine  OSV-P"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0195"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  oseltamivir carboxylate  IFD"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0205"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  induced fit docking  PBS"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0215"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  phosphate buffered saline  DMEM"  },{"  #name"  :"  keyword"  ,"  $"  :{"  id"  :"  k0225"  },"  $$"  :[{"  #name"  :"  text"  ,"  _"  :"  Dulbecco’s modified Eagle medium
本文献已被 ScienceDirect 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号