Synthesis and anticonvulsant activity of 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives

A series of novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock (MES) test, subcutaneous pentylenetetrazol (scPTZ) test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The results of these tests demonstrated that 8-heptyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-hexyloxy -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3e) were the most promising compounds, with median effective dose (ED50) of 17.6 and 17.9 mg/kg, and protective index (PI) of greater than 63.4 and 62.4 in the MES test, respectively. These PI values were higher than the PI value of the prototype antiepileptic drug carbamazepine. The scPTZ test showed that 8-pentyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3d) was the most potent with ED50 value of 38.0 mg/kg and PI value of greater than 29.4, which is much safer than marketed drug carbamazepine. The possible structure–activity relationship was discussed.

Sixteen novel 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized and their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock test, subcutaneous pentylenetetrazol test, and the rotarod neurotoxicity test.Figure optionsDownload as PowerPoint slideResearch highlights
► A series of 16 novel compounds were synthesized and chemically characterized.
► The anticonvulsant activities and neurotoxicity of the compounds were evaluated with the maximal electroshock test, subcutaneous pentylenetetrazole, and rotarod tests.
► The possible structure-activity relationship was discussed.
► The compounds showed less effective against scPTz-induced seizures. But, they exhibited a high degree of protection against scPTz-induced seizures and the maximum electric shock.