Shi-Ben Wang

Synthesis and Anticonvulsant Activity Evaluation of 5-Phenyl-(1,2,4)triazolo(4,3-c)quinazolin-3-amines

In the present study we describe the syntheses and anticonvulsant activity evaluation of 5‐phenyl‐[1,2,4]triazolo[4,3‐c]quinazolin‐3‐amine derivatives. Their anticonvulsant activity and neurotoxicity were evaluated by the maximal electroshock seizure test (MES) and the rotarod test, respectively. The majority of the compounds prepared were effective in the MES screens at a dose level of 100 mg/kg. Of these compounds, the most promising was compound 8h, which showed an ED50 value of 27.4 mg/kg and a protective index (PI) value of 5.8. These values were superior to those provided by valproate (ED50 and PI values of 272 and 1.6, respectively) in the MES test in mice. As well as its anti‐MES efficacy, the potencies of compound 8h against seizures induced by pentylenetetrazole and thiosemicarbazide were also established, with the results suggesting that the GABAergic system‐mediated mechanisms might be involved in its anticonvulsant activity.

Synthesis and evaluation of anticonvulsant and antidepressant activities of 5-alkoxytetrazolo[1,5-c]thieno[2,3-e]pyrimidine derivatives.

A series of 5-alkoxytetrazolo[1,5-c]thieno[2,3-e]pyrimidine derivatives were synthesized and their anticonvulsant and antidepressant activities were evaluated. Pharmacological tests showed that four of the synthesized compounds had weak anticonvulsant activity, while most of the compounds had excellent antidepressant activity. The most active compound was 5-(2,4-dichlorobenzyloxy)tetrazolo[1,5-c] thieno[2,3-e]pyrimidine, which decreased the immobility time by 51.62% at a dose of 100 mg/kg. The results of open-field tests of this compound indicated that it had no significant effects on the locomotor activity compared with the control group at the doses assayed in the forced swimming tests test. This means that the antidepressant activity detected in the FST for the compound is not the result of central nervous system stimulant properties, and further confirms its antidepressant-like effect.

Synthesis and anticonvulsant activities of some triazolothiadiazole derivatives.

The present study describes the synthesis and anticonvulsant activity evaluation of 6‐substituted‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives (4a–4x) and their partially dehydrogenated products 5,6‐dihydro‐6‐substituted‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole derivatives (5a–5n). The bioevaluation demonstrated that most compounds in the series of 4a–4x exhibited potent anticonvulsant activity in the maximal electroshock test. Among which, 6‐(4‐chlorophenyl)‐[1,2,4]triazolo[3,4‐b][1,3,4]thiadiazole (4h) emerged as the most promising candidate on the basis of its favorable ED50 value of 23.7 mg/kg and PI value of 10.8. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3‐mercaptopropionic acid, and bicuculline in the chemical‐induced seizure tests suggested that compound 4h displayed broad‐spectrum activity in several models, and it may exert its anticonvulsant activity through affecting the GABAergic system.

Synthesis and anticonvulsant activity of novel purine derivatives.

A series of new purines containing triazole and other heterocycle substituents was synthesized and evaluated for their preliminary anticonvulsant activity and neurotoxicity by using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) and rotarod neurotoxicity (TOX) tests. Among the compounds studied, 9-decyl-6-(1H-1,2,4-triazol-1-yl)-9H-purine (5e) was the most potent compound, with a median effective dose of 23.4 mg/kg and a high protective index of more than 25.6 after intraperitoneal administration in mice. Compound 5e showed significant oral activity against MES-induced seizures in mice, with an ED50 of 39.4 mg/kg and a PI above 31.6. These results demonstrate that compound 5e possesses better anticonvulsant activity and is safer than the commercially available drugs carbamazepine and valproate in MES, scPTZ and TOX models.

Design, Synthesis, and Anticonvulsant Activity Evaluation of 4-(3-Alkoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-ones

A series of 4‐(3‐alkoxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐ones were synthesized using the appropriate synthetic route and evaluated experimentally in the maximal electroshock test; their neurotoxicities were evaluated by the rotarod neurotoxicity test. The structures of these compounds were confirmed by IR, MS, 1H‐NMR, and elementary analysis. All target compounds exhibited anticonvulsant activity to varying degrees in the maximal electroshock test. 4‐(3‐Benzyloxy‐phenyl)‐2,4‐dihydro‐[1,2,4]triazol‐3‐one (4i) was the most promising compound with an ED50 value of 30.5 mg/kg and a protective index (PI) of 18.63, showing a higher safety than the standard carbamazepine (PI = 6.45). In addition, the potency of compound 4i against seizures induced by pentylenetetrazole and 3‐mercaptopropionic acid suggested its broad‐spectrum activity, and the mechanisms of action including inhibition of voltage‐gated ion channels and modulation of GABAergic activity might be involved in its anticonvulsant activity.

Synthesis and Anticonvulsant Activity Evaluation of 4‐Phenyl‐[1,2,4]triazolo[4,3‐a]quinazolin‐5(4H)‐one and Its Derivatives

A series of 4‐(substituted‐phenyl)‐[1,2,4]triazolo[4,3‐a]quinazolin‐5(4H)‐ones (6a–x) with triazole and other heterocyclic substituents (7–14) were synthesized and the compounds were evaluated for their anticonvulsant activity and neurotoxicity by maximal electroshock (MES) and rotarod neurotoxicity tests. Among the compounds studied, 6o and 6q showed wide margins of safety with protective indices (PIs) that were much higher than those of currently used drugs (PI6o > 25.5, PI6q > 26.0). Compounds 6o and 6q showed significant oral activity against MES‐induced seizures in mice, with ED50 values of 88.02 and 94.6 mg/kg, respectively. The two compounds were also found to have potent activity against seizures that were induced by pentylenetetrazole and bicuculline.

Synthesis and Anticonvulsant Activity Evaluation of 7-Alkoxy[1,2,4]triazolo[3,4-b]benzothiazol-3(2H)-ones

A new series of 7‐alkoxy[1,2,4]triazolo[3,4‐b]benzothiazol‐3(2H)‐ones were synthesized and evaluated for their anticonvulsant activities. Among these compounds, 7‐propoxy[1,2,4]triazolo[3,4‐b]benzothiazol‐3(2H)‐one (4c) and 7‐butoxy[1,2,4]triazolo[3,4‐b]benzothiazol‐3(2H)‐one (4d) showed the highest activity against maximal electroshock (MES)‐induced tonic extension [effective dose (ED)50: 11.4 and 13.6 mg/kg, respectively]. It is worth mentioning that compound 4d showed especially low neurotoxicity, which led to a high protective index (PI >51). The orally anticonvulsant activity data of compound 4d further confirmed its efficacy, in an MES test, and its high safety with a PI value of 50.2. In addition, the potency of compound 4h against seizures induced by pentylenetetrazole, 3‐mercaptopropionic acid, and bicuculline in the chemical‐induced seizure tests suggested that compound 4d may exert its anticonvulsant activity through affecting the GABAergic system.

Synthesis and evaluation of the anticonvulsant activity of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives

Abstract Two series of 8-alkoxy-4,5-dihydrobenzo[b][1,2,4]triazolo[4,3-d][1,4]thiazepine derivatives (6a–q and 7a–q) were synthesized and evaluated for their anticonvulsant activity using the maximal electroshock (MES) method. All of the compounds prepared were effective in the MES screens. Among which, compound 7j was considered as the most promising one with an ED50 value of 26.3 mg/kg and a superior protective index value of 12.6. The potency of compound 7j against seizures induced by pentylenetetrazole, 3-mercaptopropionic acid and bicuculline suggested that two different mechanisms of action might potentially be involved in its anticonvulsant activity, including the inhibition of voltage-gated ion channels and the modulation of GABAergic activity. A computational study was also conducted to predict the pharmacokinetic properties of the compounds prepared, with the results supporting the use of these compounds as a group of promising antiepileptic agents.

Synthesis of 4-Phenylthieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine-5(4H)-one Derivatives and Evaluation of Their Anti-inflammatory Activity

A series of 4-phenylthieno[2,3-e][1,2,4] triazolo[4,3-a]pyrimidine-5(4H)-ones (5a-p) with triazole or other heterocyclic substituents (6-11) was synthesized and the compounds were evaluated for their anti-inflammatory activity using the xylene-induced ear-edema test. Pharmacological analyses showed that the compound 4-(4-chlorophenyl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine-5(4H)-one (5m) exhibited the greatest anti-inflammatory activity (50.48% inhibition, 30 min after intraperitoneal administration) and was more potent than the reference drug, indomethacin. The peak activity of 5m was observed 4 h after oral administration, and it showed a higher anti-inflammatory activity than indomethacin did at a dose of 100 mg/kg.

Design, synthesis and anticonvulsant activity evaluation of novel 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-ones.

A series of novel 4-(4-substitutedphenyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one derivatives were synthesized and screened for their anticonvulsant activities by the maximal electroshock test (MES) and their neurotoxicity was evaluated by the rotarod neurotoxicity test (TOX). In the MES test, compound 4-{4-[(3-fluorobenzyl)oxy]phenyl}-3-methyl-1H-1,2,4-triazol-5(4H)-one (4n) was found to possess better anticonvulsant activity and higher safety than marketed drugs Carbamazepine with an ED50 value of 25.5 mg/kg and protective index (PI) value>48.8. In addition, the potency of compound 4n against seizures induced by Pentylenetetrazole, 3-Mercaptopropionic acid, and Bicuculline suggested its broad spectrum activity, and the mechanisms of action including inhibition of voltage-gated ion channels and modulation of GABAergic activity might involve in its anticonvulsant activity.