Design, synthesis and anticonvulsant evaluation of fluorinated benzyl amino enaminones.
Design, synthesis and anticonvulsant evaluation of fluorinated benzyl amino enaminones.
复制标题
氟化苄基氨基烯胺酮的设计、合成及抗惊厥作用评价。
DOI：
10.1016/j.bmc.2018.11.033
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发表时间：
2019
影响因子：
3.5
通讯作者：
Cosmas O. Okoro
中科院分区：
文献类型：
--
作者：
John Apraku;Cosmas O. Okoro
尽管新型抗癫痫药物的发现取得了进展，但癫痫仍然是一个未得到满足的医疗需求。我们合成了九种三氟甲基化烯胺酮衍生物，并使用最大电休克癫痫（MES）试验、皮下戊四唑（scPTZ）试验和旋转棒神经毒性试验测试了它们的抗惊厥活性。在测试的化合物中，3-(4-氟-3-(三氟甲基)苄氨基)-5-(三氟甲基)环己-2-烯酮(4f)，当给大鼠口服给药时，ED50为23.47mg/kg，3-(4-氯苯基氨基)-5-(三氟甲基)环己-2-烯酮(5a)，我们之前报道过，但当时没有定量数据，表现出 ED50 为 62.39mg/kg。在相同条件下，市售卡马西平的ED50为28.20mg/kg。所有测试化合物在剂量高达 300mg/kg 时均未观察到神经毒性。化合物 4f 和 5 是有待进一步开发的良好先导化合物。
Inspite of progress made for the discovery of novel antiepileptic drugs, epilepsy remains an unmet medical need. We synthesized nine trifluoromethylated enaminone derivatives and tested them for their anticonvulsant activity using maximal electroshock seizure (MES) test, subcutaneous pentylenetetrazole (scPTZ) test, and rotorod test for neurotoxicity. Among the compounds tested 3-(4-fluoro-3-(trifluomethyl)benzylamino)-5-(trifluoromethyl)cyclohex-2-enone (4f) showed ED50of 23.47 mg/kg, when given orally to rats, 3-(4-chlorophenylamino)-5-(trifluoromethyl)cyclohex-2-enone (5a), which was previously reported by us but for which no quantitative data was available at the time, exhibited an ED50of 62.39 mg/kg. Under the same conditions commercially available carbamazepine showed an ED50of 28.20 mg/kg. There were no neurotoxicity observed upto a dose of 300 mg/kg for all the tested compounds. Compounds4fand5arepresent good lead compounds for further development.