Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Hacettepe University, Ankara, Turkey.
Server Gazi Pharmacy, Merkez Efendi, Denizli, Turkey.
Drug Dev Res. 2019 Aug;80(5):606-616. doi: 10.1002/ddr.21538. Epub 2019 Apr 11.
An estimated 50 million people suffer epilepsy worldwide and 30% of the cases do not respond to current antiepileptic drugs (AEDs). Here, we report synthesis and anticonvulsant screening of new derivatives of nafimidone, a well-known member of (arylakyl)azole anticonvulsants. The compounds showed promising protection against maximal electroshock (MES)-induced seizures in mice and rats when administered via intraperitoneal (ip) and oral route. Especially, 5b, 5c, and 5i displayed outstanding activity in rats in MES test when given ip (ED : 16.0, 15.8, and 11.8 mg/kg, respectively). Additionally, 5l was active against 6 Hz and corneal-kindled mice models. Behavioral toxicity of the compounds was very low and their therapeutic indexes were high compared to some currently available AEDs. A number of pharmaceutically relevant descriptors and properties were predicted for the compounds in silico in comparison with a set of known drugs. Favorable results were obtained such as good blood-brain barrier permeability and high oral absorption, as well as drug-likeness. 5l was found to show affinity to the benzodiazepine binding site of A-type GABA receptor via molecular docking simulations.
据估计，全球有 5000 万人患有癫痫，其中 30%的病例对现有抗癫痫药物（AEDs）没有反应。在这里，我们报告了一种新型的纳非米酮衍生物的合成和抗惊厥筛选，纳非米酮是一种众所周知的（芳基烷基）唑类抗惊厥药物。这些化合物在通过腹腔内（ip）和口服途径给药时，对小鼠和大鼠的最大电休克（MES）诱导的癫痫发作显示出有希望的保护作用。特别是，当以腹腔内给药时，化合物 5b、5c 和 5i 在 MES 测试中对大鼠表现出出色的活性（ED：分别为 16.0、15.8 和 11.8mg/kg）。此外，化合物 5l 对 6 Hz 和角膜点燃的小鼠模型也具有活性。与一些现有的 AEDs 相比，这些化合物的行为毒性非常低，治疗指数很高。通过计算机模拟，对这些化合物进行了一系列与已知药物相关的药物相关描述符和性质的预测，得到了良好的结果，如良好的血脑屏障通透性和高口服吸收以及类药性。通过分子对接模拟，发现 5l 对 A 型 GABA 受体的苯二氮䓬结合位点具有亲和力。
