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 <b>6f</b> (maximal electroshock (MES), 50% effective dose (ED₅₀) = 13.1 mg/kg; subcutaneous pentylenetetrazole (scPTZ), ED₅₀ = 19.7 mg/kg) and <b>6l</b> (MES, ED₅₀ = 9.1 mg/kg; <i>sc</i>PTZ, ED₅₀ = 19.0 mg/kg) showed the best activity in MES and <i>sc</i>PTZ tests. The results of an affinity test showed that the potent compounds had better binding to the GABA_A receptors. The results of an inhibitory neurotransmitter GABA content test in brain tissue indicated that compounds <b>6f</b> and <b>6l</b> 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 <b>6f</b> and <b>6l</b> possessed anxiolytic effects, and their effects correlated with the binding sites of benzodiazepines (BZs) in the GABA_A receptors. Molecular docking was performed to investigate the interactions of the studied compound <b>6l</b> with the GABA_A receptors on the molecular level.