Department of Chemistry, S.S.G.M. College, Kopargaon, Dist-Ahmednagar, Maharashtra, 423601, India.
Syngenta Biosciences Pvt. Ltd., Santa Monica Works, Corlim, Ilhas, Goa, 403110, India.
Chem Biodivers. 2020 Sep;17(9):e2000342. doi: 10.1002/cbdv.202000342. Epub 2020 Sep 2.
A variety of 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethines and 1,3-dihydro-2H-1,4-benzodiazepin-2-one benzamide were prepared, characterized and evaluated for the anticonvulsant activity in the rat using picrotoxin-induced seizure model. The prepared 1,3-dihydro-2H-1,4-benzodiazepin-2-one azomethine derivatives emerged potentially anticonvulsant molecular scaffolds exemplified by compounds, 7-{(E)-[(4-nitrophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, 7-{(E)-[(4-bromo-2,6-difluorophenyl)methylidene]amino}-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one and 7-[(E)-{[3-(4-fluorophenyl)-1-phenyl-1H-pyrazol-4-yl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one. All these four compounds have shown substantial decrease in the wet dog shake numbers and grade of convulsions with respect to the standard drug diazepam. The most active compound, 7-[(E)-{[4-(dimethylamino)phenyl]methylidene}amino]-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one, exhibited 74 % protection against convulsion which was higher than the standard drug diazepam. Furthermore, to identify the binding mode of the interaction amongst the target analogs and binding site of the benzodiazepine receptor, molecular docking study and molecular dynamic simulation were carried out. Additionally, in silico pharmacokinetic and toxicity predictions of target compounds were carried out using AdmetSAR tool. Results of ADMET studies suggest that the pharmacokinetic parameters of all the target compounds were within the acceptable range to become a potential drug candidate as antiepileptic agents.
合成并表征了一系列 1,3-二氢-2H-1,4-苯并二氮杂酮亚胺和 1,3-二氢-2H-1,4-苯并二氮杂酮苯甲酰胺，并采用胡椒碱诱导的惊厥模型在大鼠中评估其抗惊厥活性。所制备的 1,3-二氢-2H-1,4-苯并二氮杂酮亚胺衍生物具有潜在的抗惊厥分子支架，例如化合物 7-{(E)-[(4-硝基苯基)亚甲基]氨基}-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂酮、7-[(E)-{[4-(二甲氨基)苯基]亚甲基}氨基]-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂酮、7-{(E)-[(4-溴-2,6-二氟苯基)亚甲基]氨基}-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂酮和 7-[(E)-{[3-(4-氟苯基)-1-苯基-1H-吡唑-4-基]亚甲基}氨基]-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂酮。所有这四个化合物在湿狗抖动次数和惊厥程度方面都显示出相对于标准药物地西泮的显著减少。最活跃的化合物 7-[(E)-{[4-(二甲氨基)苯基]亚甲基}氨基]-5-苯基-1,3-二氢-2H-1,4-苯并二氮杂酮，表现出 74%的抗惊厥保护作用，高于标准药物地西泮。此外，为了确定目标类似物与苯二氮䓬受体结合位点之间的相互作用结合模式，进行了分子对接研究和分子动力学模拟。此外，还使用 AdmetSAR 工具对目标化合物进行了体内药代动力学和毒性预测。ADMET 研究结果表明，所有目标化合物的药代动力学参数都在可接受范围内，有望成为抗癫痫药物的潜在候选药物。
