Design, Synthesis And Anticonvulsant Evaluation Of Triazole Derivatives

In this study, a new series of 2-substituted-7-heptyloxy-4,5-dihydro[1,2,4]triazolo [4,3-a]quinolin-1(2H)-ones (Tla-p), 1-Formamide-triazolo[4,3-a]quinoline derivatives (T2a-n),2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles (T3a-s) and 6-(3-substituted-4H-1,2,4-triazol-4-yl)-2-phenylbenzo[d]oxazoles (T4a-q) were designed and synthesized using 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (L3) and 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline (L4) as leading compound, starting form 6-hydroxyl-3,4-dihydro-2(1H)-quinoline and 2-amino-5-nitrophenol, respectively.All the structures of the synthesized compounds were characterized by 1H-NMR, IR and MS. The pharmacological experiments were carried out using (KunMing) mice in two different methods, the intraperitoneal injection and oral gavage administration. The maximal electroshock seizure test (MES) and convulsions caused by PTZ were used as anticonvulsant model experiments to evaluate the anti-epileptic activity of these new compounds. Their neurotoxicity was measured by the rotarod test (Tox).The pharmacological results showed:1. Among series T1a-p, compound Tla (with the 2acetyl-substituted group) being the most active compound. It exhibited more potent anticonvulsant activity than referenced drug carbamazepine and leading compound L3 with ED50 values of 7.2 mg/kg in anti-MES activity. But it had high neurotoxicity with TD50= 88.0 mg/kg and PI= 12.2. So, compare with T1a, T1b (with the 2-propionyl-substituted group) could be the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD50= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine.2. Among the series T2a'-n, compound 7-(hexyloxy)-4,5-dihydro-[1,2,4]triazolo [4,3-a] quinoline-1-carboxamide was the most active one. In the anti-MES test, it showed ED50=30.1 mg/kg, TD5o= 286 mg/kg, the PI value 9.5 was better than the reference drug carbamazepine with Pivalue of 6.0.3. Among the series T3a-s and T4a-q, all the synthesized compounds, compound 2-phenyl-6-(4H-1,2,4-triazol-4-yl) benzo[d]oxazole(T3a) could be the most useful and safe therapeutic compound, with ED50= 29.5 mg/kg, TD50= 285 mg/kg,and PI= 9.7, its neurotoxicity was lower than the reference drug of carbamazepine with PI value of 6.0.In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper.66 New compounds were abtained and evaluated for anticonvulsant activity, compound 7-Heptyloxy-2-propionyl-4,5-dihydro-2H-[1,2,4]triazolo[4,3-a]quinolin-l-one (Tla) was considered for the potentially most usefuland safe therapeutic compound with ED50= 8.2 mg/kg, TD5o= 318 mg/kg and PI= 39.0. Its neurotoxicity was much lower than carbamazipine. But it was lower anticonvulsant activity when oral in mice. Other work was cointinuring.