Synthesis and anticonvulsant activity of 1-(8-(benzyloxy)quinolin-2-yl)-6-substituted-4,6-diazaspiro[2,4]heptane-5,7-diones

In the present study on the development of new anticonvulsants, 16 new1-(8-(benzyloxy)quinolin-2-yl-6-substituted-4,6-diazaspiro[2,4]heptane-5,7-diones were synthesized and tested for anticonvulsant activity using the maximal electroshock (MES), subcutaneous pentylenetetrazole (scPTZ) screens, which are the most widely employed seizure models for early identification of candidate anticonvulsants. Their neurotoxicity was determined applying the rotorod test. Two compounds 8e and 8j showed promising anticonvulsant activities in both models employed for anticonvulsant evaluation. The most active compound 8e showed the MES-induced seizures with ED50 value of 8.6 mg/kg and TD50 value of 365.3 mg/kg after intraperitoneally injection to mice, which provided compound 8e with a protective index (TD50/ED50) of 26.8 in the MES test.

Graphical abstractA series of 1-(8-(benzyloxy)quinolin-2-yl)-6-substituted-4,6-diazaspiro[2,4]heptanes-5,7-diones (8a–p) were synthesized. Their anticonvulsant activity was evaluated by MES and scPTZ test, and their neurotoxicity was evaluated by the rotarod neurotoxicity test.Figure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A series of 1-(8-(benzyloxy)quinolin-2-yl-6-substituted-4,6-diazaspiro[2,4]heptanes-5,7-diones were synthesized. ► Two models have been used for determining the anticonvulsant activity of candidate compounds. ► Compound 8e showed ED50 value of 8.6 mg/kg and PI of 26.8 in the MES test. ► The structure of 1-(quinoline-2-yl)-propanespirohydantoin is a good pharmacophores with anticonvulsant activity.