Synthesis and pharmacological evaluation of novel 1'-[2-(difluoromethoxy)benzyl]-2'H,5'H-spiro[8-azabicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-diones and their derivatives

Arch Pharm (Weinheim). 2014 May;347(5):370-80. doi: 10.1002/ardp.201300289. Epub 2014 Jan 21.

Abstract

A series of novel 1'-[2-(difluoromethoxy)benzyl]-2'H,5'H-spiro[8-azabicyclo[3.2.1]octane-3,4'-imidazolidine]-2',5'-dione substituted hydantoins (5-32) were synthesized using an appropriate synthetic route and characterized by elemental analysis and spectral data. The novel molecules were screened for anticonvulsant activity in mice by maximal electroshock (MES) and subcutaneous pentylenetetrazol (ScPTZ)-induced seizure tests. The neurotoxicity was assessed using the rotarod method. Compounds 9, 10, 18, 30, and 31 exhibited anticonvulsant potency against MES seizure and in the ScPTZ model, with lesser neurotoxicity. Some title compounds showed lesser central nervous system depression compared to phenytoin.

Keywords: Anticonvulsant; Isocyanate; Maximal electroshock; ScPTZ; Spirohydantoins.

MeSH terms

  • Animals
  • Anticonvulsants / chemical synthesis*
  • Anticonvulsants / chemistry
  • Anticonvulsants / therapeutic use
  • Anticonvulsants / toxicity
  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / therapeutic use
  • Azabicyclo Compounds / toxicity
  • Behavior, Animal / drug effects
  • Imidazolidines / chemical synthesis*
  • Imidazolidines / chemistry
  • Imidazolidines / therapeutic use
  • Imidazolidines / toxicity
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity / drug effects
  • Rotarod Performance Test
  • Seizures / drug therapy
  • Spiro Compounds / chemical synthesis*
  • Spiro Compounds / chemistry
  • Spiro Compounds / therapeutic use
  • Spiro Compounds / toxicity

Substances

  • Anticonvulsants
  • Azabicyclo Compounds
  • Imidazolidines
  • Spiro Compounds