Design, Synthesis, and Pharmacological Activity of the N-(4-(1H-1,2,4-Triazol-1-yl)phenyl)-substituted-amide Derivatives

To discover novel, potent anticonvulsant compounds, a series of compounds containing triazole structural fragments were synthesized and evaluated for their anticonvulsant activity. Compounds 6f (maximal electroshock (MES), 50% effective dose (ED50) = 13.1 mg/kg; subcutaneous pentylenetetrazole (scPTZ), ED50 = 19.7 mg/kg) and 6l (MES, ED50 = 9.1 mg/kg; scPTZ, ED50 = 19.0 mg/kg) showed the best activity in MES and scPTZ tests. The results of an affinity test showed that the potent compounds had better binding to the GABAA receptors. The results of an inhibitory neurotransmitter GABA content test in brain tissue indicated that compounds 6f and 6l exerted anticonvulsant activity which may be associated with the increase of GABA content in the rat brain. Elevated plus maze (EPM) assay results showed that compounds 6f and 6l possessed anxiolytic effects, and their effects correlated with the binding sites of benzodiazepines (BZs) in the GABAA receptors. Molecular docking was performed to investigate the interactions of the studied compound 6l with the GABAA receptors on the molecular level.