Synthesis, Molecular Docking and Evaluation of 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1,3] oxazin/thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one Derivatives for their Anticonvulsant Activity
Synthesis, Molecular Docking and Evaluation of 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1,3] oxazin/thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one Derivatives for their Anticonvulsant Activity
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DOI：
10.2174/1871524917666170104142033
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发表时间：
2018-01-01
影响因子：
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通讯作者：
Singour, Pradeep K.
中科院分区：
文献类型：
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作者：
Jain, Nimisha;Jaiswal, Jugnu;Singour, Pradeep K.
背景：据世界卫生组织统计，全世界约有5000万人患有癫痫。这是由于反复发作。这些癫痫发作是由突然引起的，从短暂的注意力丧失或肌肉痉挛到严重的长时间惊厥，目的：本工作的目的是合成2-苯基取代的喹唑啉酮衍生物，并评价它们的抗惊厥和神经毒性活性。合成了一系列新的3-{4-[2-氨基-4-（取代苯基）-2H-[1.3]恶嗪/噻嗪-6-基}-2-苯基-3H-喹唑啉-4-酮衍生物，并对其抗惊厥活性进行了评价。化合物的结构经波谱分析确证。对所有合成的化合物进行分子对接，以评估它们与γ-氨基丁酸A型（GABA（A））受体的结合模式，从而以定性的方式合理化它们的抗惊厥活性。通过在任一性别的Wistar大鼠中使用（最大电休克）MES诱导的癫痫发作和皮下戊四唑（scPTZ）诱导的癫痫发作模型来筛选化合物的抗惊厥活性。所有化合物均未表现出任何神经毒性迹象。化合物3-{4-[2-氨基-4-（三氟甲基）苯基}}（4-硝基-苯基）-2H-[1，3]恶嗪-6-基} 2-苯基-3H-喹唑啉-4-酮（5a）通过MES模型和3-{4-[2-氨基-4-（三氟甲基）苯基]-2-（三氟甲基）氨基）苯甲酰胺（5a）已经显示出显著的对抗强直性癫痫发作的活性。（4-硝基-苯基）-2H-[1，3]噻嗪-6-基} 2-苯基-3H-喹唑啉-4-酮（5d）对scPTZ诱导的惊厥模型的抗惊厥作用。其中化合物5a和5d表现出较好的活性，而其他化合物的活性中等。本论文的工作是通过合成一些新的喹唑啉酮衍生物来开发和鉴定具有抗惊厥活性的新分子。
Background: According to the WHO, around 50 million people worldwide are suffering from epilepsy. It is due to the repeated occurring of seizures. These seizures are caused by sudden which may vary from a brief lapse of attention or muscle jerks, to severe and prolonged convulsions.Objectives: The aim of the present work was to synthesize 2-phenyl substituted quinazolinone derivatives and to evaluate them for anticonvulsant and neurotoxic activity.Methods: A series of novel 3-{4-[2-amino-4-(substitutedphenyl)-2H-[1.3] oxazin/thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one derivatives were synthesized and evaluated for their anticonvulsant activity. The structures of the compound have been confirmed by spectral analysis. The molecular docking was performed for all the synthesized compounds to assess their binding mode to Gamma-aminobutyric acid type A (GABA(A)) receptor in order to rationalize their anticonvulsant activities in a qualitative way. Anticonvulsant activities of compounds were screened by using (Maximal electroshock) MES induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in Wistar rats of either sex. None of the compounds demonstrated any sign of neurotoxicity.Result: Compounds 3-{4-[2-amino-4-(4-nitro-phenyl)-2H-[1, 3] oxazin-6-yl} 2-phenyl-3H-quinazolin-4-one (5a) have shown significant activity against tonic seizure by the MES model and 3-{4-[2-amino4-(4-nitro-phenyl)-2H-[1, 3] thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one (5d) against clonic seizure by scPTZ induced seizure model.Conclusion: All the newly synthesized compounds had significant anticonvulsant activity. The same two compounds 5a and 5d showed promising activity, while the other compounds have moderate activity. The proposed work is to effort towards the development and identification of novel molecules as anticonvulsant agents by the synthesis of some novel quinazolinone derivatives with improved biological activity.