Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Tehran Islamic Azad Medical Sciences University, Tehran, Iran.
Department of Pharmacology, Faculty of Medicine, Herbal Pharmacology Research Center, Tehran Medical Sciences, Islamic Azad University Tehran, Iran.
Curr Comput Aided Drug Des. 2022;18(3):159-167. doi: 10.2174/1573409918666220512000247.
Phthalimide, as the rigid form of ameltolide, exhibits a phenytoin-like profile of drug-receptor interaction and is active in the MES model and inactive in the PTZ model as an anti-epileptic agent. In this research, based on the isosteric replacement, we reported the design, preparation, and antiepileptic activity of 13 new analogs of pyrrolopyridine and isoindole.
The designed compounds were prepared by condensing 3, 4-pyridine dicarboxylic anhydride, or 4-fluorophthalic anhydride with different aryl amines. MES and PTZ-induced seizure models were utilized to evaluate the antiepileptic effect of the prepared ligands.
It was found that the prepared ligands have significantly affected both tonic and clonic seizures. In tonic seizures, the prepared compounds decreased mortality to a significant extent, and in clonic seizures, they significantly showed better frequency and latency. Compounds 9, 12, and 13 were the most potent ligands than phenytoin.
It is concluded that the best distance between two aryl parts is two bonds, and the substitution of the nitro group at the meta position of the phenyl ring is better than the para position. Our research group has investigated this concept for designing newer compounds with better anticonvulsant activity.
邻苯二甲酰亚胺作为苯妥英类似物，具有刚性结构，与药物受体相互作用表现出苯妥英样特征，作为抗癫痫药物，在 MES 模型中具有活性，而在 PTZ 模型中无活性。在这项研究中，我们基于等排替换，设计、合成了 13 种新的吡咯吡啶和异吲哚类似物，并研究了它们的抗癫痫活性。
设计的化合物通过 3,4-吡啶二甲酸酐或 4-氟邻苯二甲酸酐与不同芳基胺缩合制备得到。采用 MES 和 PTZ 诱导的癫痫发作模型评价所制备配体的抗癫痫作用。
研究发现，所制备的配体对强直和阵挛性癫痫均有显著影响。在强直发作中，所制备的化合物显著降低死亡率，在阵挛性癫痫中，它们在频率和潜伏期方面表现出更好的效果。化合物 9、12 和 13 比苯妥英的活性更强。
两个芳基部分之间的最佳距离为两个键，苯环间位取代硝基优于对位取代。我们的研究小组已经研究了这一概念，旨在设计出具有更好抗惊厥活性的新型化合物。
