Design, synthesis, and evaluation of anticonvulsant activities of benzoxazole derivatives containing the 1,2,4‐triazolone moiety

摘要

Abstract A novel series of benzoxazole derivatives containing 1,2,4‐triazolone ( 5a‐m ) was designed. These compounds were synthesized in order to screen their anticonvulsant activities by the maximal electroshock seizure (MES) model and the subcutaneous pentylenetetrazole (sc‐PTZ) seizure model in mice. The rotarod test was used to evaluate their neurotoxicities. Most of the compounds showed anti‐MES activities at 100 and 300?mg/kg. Compound 5f , which showed potential anticonvulsant activity in the MES model with ED 50 values of 22.0?mg/kg, was considered as the most promising one in this study. It exhibited greater safety than that of carbamazepine and valproate regarding neurotoxicity. The efficacy of compound 5f in inhibiting the tonic seizures and death induced by the convulsants 3‐mercaptopropionic acid and BIC was also verified. In an enzyme‐linked immunosorbent assay, compound 5f and the positive drug phenytoin significantly increased the γ‐aminobutyric acid (GABA) level in the mouse brain. Further, pretreatment with an inhibitor of the GABA synthesizing enzyme dramatically raised the ED 50 value of 5f in the MES model. These results confirmed that the compound 5f plays its anticonvulsive action via regulating the GABA function in the brain. Also, a docking study of the compound 5f in the benzodiazepine (BZD) binding site of the GABA A receptor confirmed possible binding of the compound 5f with BZD receptors.