Structural Modifications And Pharmacological Activity Evaluation Of Anticonvulsant Lead Triazoles

In this study, we designed and synthesized six series of triazole derivatives (W1-W6):5-phenyl-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-α]pyridine (W1), 5-alkoxythieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (W2),7-alkyl-7H-[1,2,4]triazo-lo[4,3-g]purine (W3), 1-alkoxy-4-(1H-1,2,4-triazol-1-yl)phthalazine (W4),8-alkoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (W5),9-alkyl-6-(1H-1,2,4-triazol-1-yl)-9H-purine (W6), using 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoline (Ⅱ) as leading compound. The structures of the target compounds were confirmed by 1H-NMR, MS, and IR techniques. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure (MES) test and the rotarod test. According to the result of preliminary screening, the potent compounds were subjected to further studies for quantification of their anticonvulsant activity (ED50) and neurotoxicity (TD50) in mice, and calculated the value of protective index (PI=TD50/ED50). In order to speculate the possible mechanism of anticonvulsant activity, compounds 5-(4-chlorophenyl)-4,5-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyridine (W-lc), 5-(3-chlorophenoxy)thieno[2,3-e][1,2,4]triazolo[4,3-c]pyrimidine (W-2c) and 8-octoxy-5-(4H-1,2,4-triazol-4-yl)quinoline (W-5g) were used in chemical substances (pentylenetetrazole,3-mercaptopropionic acid and bicuculline) induced seizure tests.Pharmacological analyses showed that most of the test compounds exhibited anticonvulsant activity in different doses. Among the tested compounds, serveral compounds were found to be especially potent. Quantitative assessment of the compounds after intraperitoneal administration in mice showed that the most active compound was W-1c with ED50 values of 27.4 mg/kg (MES). Although the anticonvulsant activity of compound W-lc ED50 is higher than marketed drug carbamazepine (9.8 mg/kg), but it possessed lower neurotoxicity with PI value of 16.6, which was safer than positive control drug. In series of W4-W6, another candidate compound is compound W-5g, with ED50 values of 8.8 mg/kg, which was also safer than positive control carbamazepine.The result of chemical substances induced seizure models showed that compounds W-1c, W-2c, and W-5g can inhibited tonic seizures and reduced the mortality of mice. Therefore, we can speculate that the mechanism of action of these three compounds might inhibit chemical substances-induced seizures in mice by enhancing GABAergic neurotransmission, enhancing GABAergic level or modulating the GABAA receptor.In a word, we designed and synthesized six series of triazole derivatives (W1-W6) using 7-alkoxy-4,5-dihydro[1,2,4]triazolo[4,3-α]quinoline (Ⅱ) as leading compound. The structures of the target compounds were confirmed by spectral techniques. Meanwhile, all the target compounds were evaluated their anticonvulsant activities by the MES test. According to the result of MES screening, the potent compounds were subjected to further research to speculate the possible mechanism of anticonvulsant activity. According to the result of preliminary anticonvulsant activity, the structure-activity relationships of the target compounds were obtained.