Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University) , New Delhi , India.
J Enzyme Inhib Med Chem. 2014 Aug;29(4):505-16. doi: 10.3109/14756366.2013.815177. Epub 2013 Aug 5.
A series of novel (5-amino-3-substituted-1, 2, 4-triazin-6-yl) (2-(6-halo-substituted benzo[d]isoxazol-3-yl) pyrrolidin-1-yl) methanone 5a-5r was synthesized. Their anticonvulsant activities were evaluated by the maximal electroshock (MES) test and neurotoxicity was evaluated by the rotorod test. The MES test showed that (5-amino-3-phenyl-1, 2, 4-triazin-6-yl)(2-(6-fluorobenzo[d]isoxazol-3-yl) pyrrolidin-1-yl) methanone 5c was found to be the most potent compound with ED50 value of 6.20 mg/kg (oral/rat) and a protective index (PI = ED50/TD50) value of >48.38, which was much higher than the PI of the reference drug phenytoin. To explain the possible mechanism of action of selected derivatives 5 b, 5 c, 5 i and 5 o, their influence on sodium channel was evaluated in vitro.
合成了一系列新型（5-氨基-3-取代-1,2,4-三嗪-6-基）（2-（6-卤代苯并[d]异噁唑-3-基）吡咯烷-1-基）甲酮 5a-5r。通过最大电休克（MES）试验评估了它们的抗惊厥活性，通过旋转棒试验评估了神经毒性。MES 试验表明，（5-氨基-3-苯基-1,2,4-三嗪-6-基）（2-（6-氟苯并[d]异噁唑-3-基）吡咯烷-1-基）甲酮 5c 是最有效的化合物，其 ED50 值为 6.20mg/kg（口服/大鼠），保护指数（PI=ED50/TD50）值>48.38，远高于参考药物苯妥英的 PI。为了解释选定的衍生物 5b、5c、5i 和 5o 的可能作用机制，在体外评估了它们对钠通道的影响。
