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Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones

Authors :
Ming-Xia Song
Zhen-Yuan Wang
Shi-Hui He
Sheng-Wang Yu
Shi-Long Chen
Dong-Fu Guo
Wen-Hao Zhao
Xian-Qing Deng
Source :
Molecules, Vol 23, Iss 4, p 756 (2018)
Publication Year :
2018
Publisher :
MDPI AG, 2018.

Abstract

In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a–m) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23.7 and 18.9 mg/kg, respectively. The TD50 value of 4g was 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound 4g significantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of 4g in the MES model, which suggests that the mechanism through which compound 4g elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.

Details

Language :
English
ISSN :
14203049
Volume :
23
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Molecules
Publication Type :
Academic Journal
Accession number :
edsdoj.89f4ae8c9f60474eb9c77bdbc6c4c5ac
Document Type :
article
Full Text :
https://doi.org/10.3390/molecules23040756