Design, Synthesis And Anticonvulsant Activity Evaluation Of 6-Alkoxy-[1,2,4]triazolo[3,4-a]phthalazin-3(2H)-ones

A new series of 6-alkoxy-[1,2,4]triazolo[3,4-a]phthalazin-3(2H)-one derivatives (5a-5r) was synthesized in this paper by condensation of appropriate 1-chloro-4-alkoxyphthalazine with methyl hydrazine carboxylate in dimethyl sulfoxide. All the compounds 5a-5r, characterized by IR,'H-NMR and mass spectrometry, have been evaluated for their anticonvulsant activity against MES-induced seizure and their neurotoxicity in rotarod test. The results illustrated that most of the synthesized compounds exhibited moderate anticonvulsant activity against MES-induced seizure at the concentration of 300 mg/kg, while only 5b,5c, 5j,5n and 5p displayed the potency of anticonvulsant at 100 mg/kg in MES test. Among all the compounds,6-pentyloxy-[1,2,4]triazolo[3, 4-a]phthalazin-3(2H)-one (5b) unfolded the most potential anticonvulsant activity against MES-induced seizure, and showed potency of anticonvulsant after administrated 4 hours, with ED50 value of 93.0 mg/kg and TD50 value of 131.4 mg/kg; so, a small protective index (PI) value of 1.4 was gained.In conclusion, most of these compounds possessed the weak or moderate anticonvulsant effect even under the large dose of 300mg/kg, which went beyond the previously designed expectation. It is possible that triazolone incorporation into the substituted phthalazine led to dramatic reduction in the lipophilicity of the compounds and made it difficult for the target compounds to pass biological membranes.