Study On The Syntheses And Anticonvulsant Activity Of 1,2,4-Triazolpyrimidines

Epilepsy is a common nervous system disease,which affects the health of 1-2%of the world's population.At present,most of the anticonvulsant drugs used in clinic show low efficacy and side effects.Therefore,it is of great significance to seek and develop effective and low toxic anticonvulsant compounds.Two novel1,2,4-triazopyrimidone compounds with excellent activity in vitro were found in our previous studies on anticonvulsant compounds,but they show poor activity in vivo due to their poor solubility.In order to obtain anticonvulsant compounds with better activity in vivo,the analogues and derivatives of 1,2,4-triazopyrimidone are designed and synthesized.The anticonvulsant activities are screened in vitro and in vivo.Compounds of 1,2,4-triazopyrimidone and 7-alkane?benzo?oxo-1,2,4-triazo pyrimidine are designed.Among them,22 kinds of 1,2,4-triazolopyrimidinone compounds are synthesized by amidation,cyclization and condensation cyclization using acid chloride and aminoguanidine as raw materials;18 kinds of7-alkane?benzo?oxo-1,2,4-triazole are prepared by chlorination of carbonyl groups of two 1,2,4-triazopyrimidones with good activity in vitro and then reaction with phenol and alcohol.All compounds are new compounds and their structures are confirmed by nuclear magnetic resonance and mass spectrometry.Among them,there are eleven compounds of 1,2,4-triazopyrimidone and eight compounds of 7-alkoxy-1,2,4-triazopyrimidine show good activity in epilepsy model induced by 4-AP in vitro,its IC₅₀0 values are between 0.33-5.44?M and 1.81-3.33?M,respectively,which are significantly better than the positive control drugs carbamazepine?35?M?.Compounds Vc and Ve show the excellent anticonvulsant activity with IC₅₀0 of 0.36 and 0.45?M,respectively.In vivo epilepsy?subcutaneous pentylenetetrazole?model,19 active compounds show different degrees of anticonvulsant activity,of which 14 compounds show very good anticonvulsant activity at a dose of 100 mg/kg and different degrees of anticonvulsant activity at a dose of 30 mg/kg,which are much better than that of the positive control drugs carbamazepine and phenytoin sodium?both?100 mg/kg?,compounds Xf and Xn showed excellent anticonvulsant effects at the dose of 30 mg/kg.The preliminary structure-activity relationship indicate that adding a carbon chain to the pyrimidone or triazole ring of 1,2,4-triazopyrimidone compounds is beneficial to their anticonvulsant activity,which may be due to the fact that the increase of carbon chain destroys the planarity of the whole molecule and thus improves its solubility;the introduction of fluorine atoms into benzene ring decreases its anticonvulsant activity.7-heptanoxo-1,2,4-triazopyrimidinesin7-alkoxy-1,2,4-triazopyrimidineshowthebest anticonvulsant activity.The introduction of heptaoxyl group is beneficial to the anticonvulsant activity,which may be due to the improvement of lipid-water partition coefficient of the compounds by heptaoxyl group.In order to study its possible mechanism,docking studies were carried out on GABA molecular model.The results of docking are in good agreement with the experimental results in vivo,it was speculated that the anticonvulsant effects of these compounds might be related to GABA targets.The results of this study is valuable for research and development of new anticonvulsant compounds with high efficiency and low toxicity.