Synthesis Of4-(Alkoxy-Phenyl)-2.4-Dihydro-3H-[1,2,4]Triazol-3-Ones Derivatives And The Antiepileptic Activity Study

In this study, twenty compounds of4-(3-alkoxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (5a-5t) and twenty-one compounds of4-(2-alkoxy-phenyl)-2,4-dihydro-3H,2,4-triazol-3-ones (10a-10u) were designed and synthesized by using3-aminophenol and2-aminophenol as started materials. All the structures of the synthesized compounds were characterized by IR,1H-NMR and MS.Their anticonvulsant activities were evaluated experimentally against maximal electroshock test and their neurotoxicities were evaluated under the rotarod neurotoxicity test with intraperitoneally injected mice. The pharmacological results showed that all the synthesized compounds exhibited anticonvulsant activity in varying degrees against the MES. As the ring-opened compounds of the leading structrure of8-benzyloxy-4,5-dihydro-[1,2,4]triazole[4,3-α]quinoline-1(2H)-one (Ⅲ-h),4-(3-benzyloxy-phenyl)-2,4-dihydro-3H-[1,2,4]triazol-3-one (5i) was the most promising compound with an ED50value of30.5mg/kg, and protective index (PI) of18.63. Among the ectopic substituted compounds5a-5t,4-(2-octyloxy-phenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (10g) was the most promising compound with an median effective dose (ED50) of23.7mg/kg, the median toxicity dose (TD50) of611.0. mg/kg and the protective index (PI) of25.8, which showed the higher safety than the standard carbamazepine (PI=6.5).In addition, as well as demonstrating the anti-MES efficacy of compound5i and10g, its potency against seizures induced by pentylenetetrazole,3-mercaptopropionic acid and bicuculline were also established. With the results suggesting that GABA-mediated mechanisms might be involved in anticonvulsant activity of compound5i and10g, such as enhancing GABAergic mediated mechanism or modulating the GABAA receptor.