Synthesis and anticonvulsant activity evaluation of 7-alkoxy-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]thiazin-1-ones in various murine experimental seizure models

A novel series of 7-alkoxy-2,4-dihydro-1H-benzo[b][1,2,4]triazolo[4,3-d][1,4]-thiazin-1-ones have been synthesized and tested for their anticonvulsant activity using the maximal electroshock (MES) method. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of the compounds tested, the most promising was 7-[(4-fluorobenzyl)oxy]-2,4-dihydro-1H-[1,2,4]-triazolo[4,3-d][1,4]-benzothiazin-1-one (6m), which showed an ED50 value of 9.2 mg/kg in the MES test in mice. Furthermore, the compound exhibited a PI value of 15.4 which was superior to the standard drug carbamazepine (PI value of 6.4). As well as demonstrating the anti-MES efficacy of compound 6m, its potency against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid, and bicuculline were also established, with the results suggesting that several different mechanisms of action might be involved in its anticonvulsant activity, including the inhibition of voltage-gated ion channels and the modulation of GABAergic activity.