5,6-Dihydropyrimidine-1(2H)-carbothioamides: Synthesis, in vitro GABA-AT screening, anticonvulsant activity and molecular modelling study

Bioorg Chem. 2018 Apr:77:56-67. doi: 10.1016/j.bioorg.2017.12.031. Epub 2018 Jan 2.

Abstract

Even after considerable advances in the field of epilepsy treatment, convulsions are inefficiently controlled by standard drug therapy. Herein, a series of pyrimidine-carbothioamide derivatives 4(a-t) was designed as anticonvulsant agents by doing some important structural modifications in well-known anticonvulsant drugs. Two classical animal models were used for the in vivo anticonvulsant screening, maximum electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models; followed by motor impairment study by rotarod method. The most active compound 4g effectively suppressed seizure effect in both the animal models with median doses of 15.6 mg/kg (MES ED50), 278.4 mg/kg (scPTZ ED50) and 534.4 mg/kg (TD50) with no sign of neurotoxicity. Furthermore, in vitro GABA-AT enzyme activity assay of 4g showed inhibitory potency (IC50) of 12.23 μM. The docking study also favored the animal studies.

Keywords: Anticonvulsant activity; Carbothioamides; GABA-AT; In vitro; Pyrimidine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Aminobutyrate Transaminase / antagonists & inhibitors*
  • 4-Aminobutyrate Transaminase / metabolism
  • Animals
  • Anticonvulsants / chemical synthesis
  • Anticonvulsants / chemistry
  • Anticonvulsants / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Electroshock
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Male
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Pentylenetetrazole
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Seizures / chemically induced
  • Seizures / drug therapy*
  • Structure-Activity Relationship
  • Thioamides / chemical synthesis
  • Thioamides / chemistry
  • Thioamides / pharmacology*

Substances

  • 5,6-dihydropyrimidine-1(2H)-carbothioamide
  • Anticonvulsants
  • Enzyme Inhibitors
  • Pyrimidines
  • Thioamides
  • 4-Aminobutyrate Transaminase
  • Pentylenetetrazole