Jain Nimisha, Jaiswal Jugnu, Pathak Ashish, Singour Pradeep K
Computational & Synthetic Chemistry Division, Department of Pharmaceutical Chemistry, VNS Group of Institutions- Faculty of Pharmacy, Neelbud, Bhopal- 462023 (M.P.), India.
Computational & Synthetic Chemistry Department, Ravishankar college of Pharmacy, Bhopal-462044 (M.P.), India.
Cent Nerv Syst Agents Med Chem. 2018 Jan 26;18(1):63-73. doi: 10.2174/1871524917666170104142033.
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.
The aim of the present work was to synthesize 2-phenyl substituted quinazolinone derivatives and to evaluate them for anticonvulsant and neurotoxic activity.
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 (GABAA) 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.
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-amino- 4-(4-nitro-phenyl)-2H-[1, 3] thiazin-6-yl} 2-phenyl-3H-quinazolin-4-one (5d) against clonic seizure by scPTZ induced seizure model.
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.
根据世界卫生组织的数据，全球约有5000万人患有癫痫。这是由于癫痫发作反复发生所致。这些发作是由突然发作引起的，其表现形式多样，从短暂的注意力不集中或肌肉抽搐，到严重且持续的惊厥。
本研究的目的是合成2-苯基取代的喹唑啉酮衍生物，并评估它们的抗惊厥和神经毒性活性。
合成了一系列新型的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，并评估其抗惊厥活性。通过光谱分析确定了化合物的结构。对所有合成化合物进行分子对接，以评估它们与A型γ-氨基丁酸（GABAA）受体的结合模式，从而从定性角度解释它们的抗惊厥活性。使用最大电休克（MES）诱导的癫痫发作和皮下注射戊四氮（scPTZ）诱导的癫痫发作模型，在不同性别的Wistar大鼠中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-(4-硝基苯基)-2H-[1,3]恶嗪-6-基]}2-苯基-3H-喹唑啉-4-酮（5a）在MES模型中对强直发作显示出显著活性，而化合物3-{4-[2-氨基-4-(4-硝基苯基)-2H-[1,3]噻嗪-6-基]}2-苯基-3H-喹唑啉-4-酮（5d）在scPTZ诱导的癫痫发作模型中对阵挛发作显示出显著活性。
所有新合成的化合物均具有显著的抗惊厥活性。相同的两种化合物5a和5d显示出有前景的活性，而其他化合物具有中等活性。本研究旨在通过合成一些具有改善生物活性的新型喹唑啉酮衍生物，努力开发和鉴定新型抗惊厥分子。
