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目的设计合成一系列4-(4-烷氧基苄基/苯乙基)-2H-1,2,4-三唑-3(4H)-酮类化合物,并评价其抗惊厥活性和神经毒性。方法以对羟基苄胺和对羟基苯乙胺为起始原料,通过氨基保护、羟基烷基化、氨基脱保护以及氨基成三唑酮环反应合成目标化合物。采用最大电惊厥实验(MES)评价化合物的抗惊厥活性,采用旋转棒法测定其神经毒性。结果与结论合成了26个未见文献报道的新化合物,其结构经IR、1H-NMR、13C-NMR和EI-MS谱确证。活性实验结果表明,所有化合物在不同剂量下都显示出抗惊厥活性。其中,4-[4-(3-氟苄氧基)苯乙基]-2H-1,2,4-三唑-3(4H)-酮(9f)的活性最强,其半数有效量ED50值为19.5 mg·kg-1,保护指数(PI)为5.1。该化合物的PI值高于阳性对照药丙戊酸钠,低于卡马西平。
Aim To design and synthesize a series of 4- (4-alkoxybenzyl / phenethyl) -2H-1,2,4-triazol-3 (4H) -ones and evaluate their anticonvulsant activity and neurotoxicity . Methods The target compounds were synthesized from p-hydroxybenzylamine and p-hydroxy-phenethylamine by amino-protection, hydroxyalkylation, amino deprotection and amino-triadimefon reaction. The anticonvulsant activity of the compound was evaluated using maximal electroconvulsive assay (MES) and its neurotoxicity was determined using a rotarod. RESULTS AND CONCLUSION Twenty six new compounds were synthesized and their structures were confirmed by IR, 1H-NMR, 13C-NMR and EI-MS. The results of the activity experiments showed that all the compounds showed anticonvulsant activity at different doses. Among them, the activity of 4- [4- (3-fluorobenzyloxy) phenethyl] -2H-1,2,4-triazol-3 (4H) -one (9f) The value was 19.5 mg · kg-1, and the protection index (PI) was 5.1. The PI value of this compound is higher than the positive control drug valproate, lower than carbamazepine.