Quinolinone Derivatives And Antiepileptic Effects

To search for new anticonvulsant agents with enhanced efficacy and minimal side effect, we designed and synthesized 30 compounds including 6-alkoxyl-3,4-dihydro-2 (1H) -quinolinones (2a-2n), l-substituted-7-benzyloxyl-4,5-dihydro-[l,2,4]triazolo [4,3-a]quinolinones (5a-5n), and 7-benzylamino-4,5-dihydro-[l,2,4]triazolo[4,3-a] quinolinones using 3,4-dihydro-2(1H)-quinolinone as the lead compound. Structures of the synthesized compounds were confirmed by ~1H-NMR, IR, and MS spectra. Their anticonvulsant activity was evaluated by maximal electrolshock (MES) test and subcutaneous pentylenetetrazole (sc-Met) test. And their neurotoxicity was measured by rotarod test (Tox).6-Alkyloxyl-3,4-dihydro-2(1H)-quinolinones (2a-2n) were prepared by structure-modulating of 3,4-dihydro-2(1H)quinolinone and were screened for anticonvulsant activity. The result showed that compound 2f, which was 6-Hexyloxy-3,4-dihydro-2 (1H)-quinolinone, was quite effective in anti-MES test with ED50 of 29.6 mg/kg and no neurotoxicity was observed even under 300mg/kg. This, in sequence, resulted in a PI value of greater than 10, which was preferable to Phenobarbital, Carbamazepin, and Sodium valproate.According to the structure mosaic theory, we incorporate triazole in the 1 and 2 position of 3,4-dihydro-2(1H)-quinolinone to optimize the anticonvulsant activity of compound 2f. And in the meantime, to study the influence of different substituent on the first position on its anticonvulsant activity, we synthesized fourteen l-substituted-7-benzyloxyl-4,5-dihydro [l,2,4]triazolo[4,3-a]quinolinones. The most active compound was 7-Benzyloxy- 4,5-dihydro-[ 1,2,4] triazolo[4,3-a]quinoline, compound 5a, with ED50 of 17.3 and PI of 3.5 in MES test. It was more potent than phenobarbital and sodium valproate in anti-MES activityIn respect of the theory of bioisosterism, we designed compound 9and 10 by substitute -NH- for -O- to further improve the activity of compound 5a. With ED50 of 6.5 mg/kg, compound 9 exhibited more significant activity than compound 5a. Its TD50 was 54.8 mg/kg, leaving its PI of 8.4, which was better than carbamazepine.