Background: Epilepsy and depression are two of the common diseases seriously threatening
life and health of human. A shared neurobiological substrate led to the bidirectional relationship and high
comorbid occurrence of the two disorders. Recently, an increasing number of patients with epilepsy (PWE)
require some form of antidepressant medication. However, most of the available antidepressants are
inadequate for PWE for some reasons. So, the search for novel and increasingly effective drugs with
anticonvulsant and antidepressant activities is necessary.
Methods: A series of 2-substituted-6-(4H-1,2,4-triazol-4-yl)benzo[d]oxazoles (5a-p) were designed and
synthesized. Their anticonvulsant activities were evaluated using maximal electroshock shock (MES) and
subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. Their antidepressant activities were
screened with the forced swimming test (FST).
Results: All the compounds showed anti-MES activities in different degree, among which 5g and 5j
were the most promising one with ED50 value of 31.7 and 12.7 mg/kg, respectively. What’s more, 5g
and 5j also exhibited nice anti-scPTZ activities and low neurotoxicity. Interestingly, these compounds
also showed good antidepressant activities in FST. And the efficacy of 5g were also confirmed by a tail
suspension test and a open field test. The pretreatment of thiosemicarbazide (an inhibitor of γ-
aminobutyric acid synthesis enzyme) significantly increased the ED50 of 5g in MES and reversed the
reductions in the immobility time of 5g in FST.
Conclusion: Triazole-containing benzo[d]oxazole is a good skeleton to develop compounds with both
anticonvulsant and antidepressant activities. We have got the compound 5g, which display remarkable
antidepressant and anticonvulsant activities, and the GABAergic system was involved in the action
mechanism of 5g.