To further investigate anticonvulsant activity of quinoline derivatives, a series of 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one derivatives was synthesized starting from 7-hydroxyl-3,4-dihydro-2(1H)-quinoline. In initial (phase I) screening and quantitative (phase II) evaluation, compound 7-benzyloxyl-4,5-dihydro-[1,2,4]thiazolo[4,3-a]quinoline-1(2H)-one (3f) was among the most active but also has the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED(50)) of 12.3 mg/kg, median toxicity dose (TD(50)) of 547.5 mg/kg, and the protective index (PI) of 44.5, which is much greater than PI of the prototype drugs phenytoin, phenobarbital, carbamazepin, and valproate. Compound 3f was chosen for further evaluation. In phase III pharmacological test, the compound had median hypnotic dose (HD(50)) and median lethal dose (LD(50)) of 1204 mg/kg and >3000 mg/kg, respectively, thus demonstrating much greater margin of safety compared to prototype drugs. The compound 3f also showed significant oral activity against MES-induced seizures and low oral neurotoxicity in mice in phase IV pharmacological test. Possible structure-activity relationship was discussed.