Guo Li-Jun, Wei Cheng-Xi, Jia Jing-Hao, Zhao Li-Ming, Quan Zhe-Shan
Key Laboratory of Organism Functional Factors of the Changbai Mountain, Yanbian University, Ministry of Education, Yanji, Jilin 133002, China.
Eur J Med Chem. 2009 Mar;44(3):954-8. doi: 10.1016/j.ejmech.2008.07.010. Epub 2008 Jul 19.
A series of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives were synthesized using 4-hydroxyquinolin-2(1H)-one as the starting material. Their anticonvulsant activities were evaluated by the maximal electroshock test (MES) and their neurotoxicities were measured by the rotarod test. The results of these tests demonstrated that 5-hexyloxy-[1,2,4]triazolo[4,3-a]quinoline (3f) was the most potent anticonvulsant, with median effective dose (ED(50)) of 19.0mg/kg and protective index (PI=TD(50)/ED(50)) values of 5.8 in the MES test. Compound 5-benzyloxy-[1,2,4]triazolo[4,3-a]quinoline (3j), exhibited a little weaker activity than compound 3f in controlling the seizure induced by MES test at the dose of 22.8 mg/kg, but it possessed lower neurotoxicity with PI value of 12.0, which was safer than marketed drug carbamazepine. To explain the possible mechanism of anticonvulsant activity, compound 3j was tested in pentylenetetrazole test, isoniazid test, thiosemicarbazide test, 3-mercaptopropionic acid and strychnine test.
以4-羟基喹啉-2(1H)-酮为起始原料，合成了一系列5-烷氧基-[1,2,4]三唑并[4,3-a]喹啉衍生物。通过最大电休克试验（MES）评估其抗惊厥活性，并通过转棒试验测量其神经毒性。这些试验结果表明，5-己氧基-[1,2,4]三唑并[4,3-a]喹啉（3f）是最有效的抗惊厥剂，在MES试验中的半数有效剂量（ED(50)）为19.0mg/kg，保护指数（PI = TD(50)/ED(50)）值为5.8。化合物5-苄氧基-[1,2,4]三唑并[4,3-a]喹啉（3j）在22.8mg/kg剂量下控制MES试验诱发的癫痫发作时，活性略低于化合物3f，但具有较低的神经毒性，PI值为12.0，比市售药物卡马西平更安全。为了解释抗惊厥活性的可能机制，在戊四氮试验、异烟肼试验、氨基硫脲试验、3-巯基丙酸试验和士的宁试验中对化合物3j进行了测试。
