Anticonvulsant evaluation of clubbed indole-1,2,4-triazine derivatives: a synthetic approach

Eur J Med Chem. 2014 Jun 10;80:509-22. doi: 10.1016/j.ejmech.2014.04.043. Epub 2014 Apr 15.

Abstract

A series of thirty indole C-3 substituted 5-amino-6-(5-substituted-2-phenyl-1H-indol-1-yl)-4,5-dihydro-1,2,4-triazine-3(2H)-thione 5a-f, 6a-f, 7a-f, 8a-f and 9a-f were synthesized to explore prospective anticonvulsant agents. The derivative 1-(1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indol-3-yl)ethanone (6b) had significant activity in maximal electroshock test with minimal duration of limb extension (5.40 ± 0.61 s) and quantitative median dose of 7 mg/kg. In subcutaneous pentylenetetrazole screen 1-(5-amino-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-6-yl)-5-fluoro-2-phenyl-1H-indole-3-sulfonamide (7b) increased the seizure latency to onset of clonus and was effective at a median dose of 35 mg/kg. An in vitro radioligand binding assay on sodium channel and γ-amino butyric acid estimation was also performed on active compounds to perceive the mechanistic procedure responsible for it action.

Keywords: Anticonvulsant; GABA; Quantification; Sodium channel; Triazine.

MeSH terms

  • Animals
  • Anticonvulsants / adverse effects
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry*
  • Anticonvulsants / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Chemistry Techniques, Synthetic
  • Male
  • Mice
  • Motor Activity / drug effects
  • Sodium Channels / metabolism
  • Triazines / adverse effects
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / pharmacology*
  • gamma-Aminobutyric Acid / metabolism

Substances

  • Anticonvulsants
  • Sodium Channels
  • Triazines
  • 1,2,4-triazine
  • gamma-Aminobutyric Acid