1,2,4-三唑并[4,3-a]喹啉衍生物的合成及其抗惊厥活性

目的 设计合成一系列1,2,4-三唑并4,3-a]喹啉衍生物,并评价其抗惊厥活性和神经毒性.方法 以4-羟基喹啉-2(1H)酮为起始原料,经烷基化、氯代、肼代、环合等反应合成1,2,4-三唑并4,3-a]喹啉衍生物.通过最大电惊厥实验(MES)和旋转棒法(Rotarod),分别测定目标化合物的抗惊厥活性和神经毒性....

Synthesis and anticonsulvant activity of 1,2,4-triazolo[4,3-a]quinolines

In our previous work,5-hexyloxy-1,2,4]triazolo4,3-a]quinoline（compoundⅠ） showed potent anticonvulsant activity,with ED50 value of 19.0 mg · kg-1 and protective index（PI=TD50/ED50） values of 5.8 in the MES test.As part of our continuous effort to find better anticonvulsant candidate in this area,twelve derivatives of leading compound Ⅰ were synthesized by the modification of 1,2,and 5 positions of it.In addition,their anticonvulsant activity and neurotoxicity were evaluated using the MES test and the rotarod test in mice,respectively.In the same condition,the 50%toxic dose（TD50） and 50% effective dose（ED50） of the reference drugs carbamazepine and the leading compoundⅠwere evaluated in MES test and the rotarod test in our laboratory.The results of pharmacological tests demonstrated that some target compounds（6a,10a,10b） displayed anticonvulsant activities in different doses,and 5-hexyloxy-1-methyl-1,2,4]triazolo4,3-a]quinoline（10b） showed good activity with an ED50 value of 18.0 mg · kg-1 and protective index（PI=TD50/ED50） value of 7.9.The anticonvulsant activity（ED50 and PI） of 10b is better than that of the leading compoundⅠ.Compared to the reference drugs,compound 10b exhibited the weaker acti-vity,while it possessed the higher PI value,which mean that compound 10b is safer than marketed drug carbamazepine.