Department of Pharmaceutical Chemistry, Faculty of Pharmacy Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy Jamia Hamdard (Hamdard University), New Delhi 110062, India.
Eur J Med Chem. 2014 Sep 12;84:42-50. doi: 10.1016/j.ejmech.2014.07.016. Epub 2014 Jul 8.
A series of 3-(benzo[d]isoxazol-3-yl)-N-substituted pyrrolidine-2, 5-dione (7a-7d, 8a-8d, 9a-9c) have been prepared and evaluated for their anticonvulsant activities. Preliminary anticonvulsant activity was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) tests after intraperitoneal (ip) injection into mice, which are the most widely employed models for early identification of anticonvulsant candidate. The acute neurological toxicity (NT) was determined applying rotorod test. The quantitative evaluation after oral administration in rats showed that the most active was 3-(benzo[d]isoxazol-3-yl)-1-(4-fluorophenyl) pyrrolidine-2, 5-dione (8a) with ED50 values of 14.90 mg/kg. Similarly the most potent in scPTZ was 3-(benzo[d]isoxazol-3-yl)-1-cyclohexylpyrrolidine-2, 5-dione (7d) with ED50 values of 42.30 mg/kg. These molecules were more potent and less neurotoxic than phenytoin and ethosuximide which were used as reference antiepileptic drugs.
已经合成了一系列 3-(苯并[d]异噁唑-3-基)-N-取代的吡咯烷-2,5-二酮（7a-7d、8a-8d、9a-9c），并评估了它们的抗惊厥活性。初步的抗惊厥活性是通过腹腔内（ip）注射后在小鼠中进行最大电休克（MES）和皮下戊四氮（scPTZ）测试来评估的，这是早期鉴定抗惊厥候选药物最广泛使用的模型。急性神经毒性（NT）通过转棒测试来确定。在大鼠中进行的口服定量评估表明，最活跃的是 3-(苯并[d]异噁唑-3-基)-1-(4-氟苯基)吡咯烷-2,5-二酮（8a），其 ED50 值为 14.90 mg/kg。同样，在 scPTZ 中最有效的是 3-(苯并[d]异噁唑-3-基)-1-环己基吡咯烷-2,5-二酮（7d），其 ED50 值为 42.30 mg/kg。这些分子比苯妥英和乙琥胺更有效且神经毒性更小，苯妥英和乙琥胺被用作参考抗癫痫药物。
