Abuelizz Hatem A, Dib Rabab El, Marzouk Mohamed, Anouar El-Hassane, A Maklad Yousreya, N Attia Hanan, Al-Salahi Rashad
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11495, Saudi Arabia.
Molecules. 2017 Jun 30;22(7):1094. doi: 10.3390/molecules22071094.
A new series of quinazoline-4(3H)-ones are evaluated for anticonvulsant activity. After intraperitoneal (ip) injection to albino mice at a dose of 100 mg/kg body weight, synthesized quinazolin-4(3H)-ones (1-24) were examined in the maximal electroshock (MES) induced seizures and subcutaneous pentylenetetrazole (scPTZ) induced seizure models in mice. The Rotarod method was applied to determine the neurotoxicity. Most of the compounds displayed anticonvulsant activity in the scPTZ screen at a dose range of 0.204-0.376 mmol/mL. Out of twenty-four, compounds 8, 13 and 19 proved to be the most active with a remarkable protection (100%) against PTZ induced convulsions and four times more potent activity than ethosuximide. The structure-activity relationship concluded valuable pharmacophoric information, which was confirmed by the molecular docking studies using the target enzyme human carbon anhydrase II (HCA II). The studied quinazoline analogues suggested that the butyl substitution at position 3 has a significant effect on preventing the spread of seizure discharge and on raising the seizure threshold. However, benzyl substitution at position 3 has shown a strong anticonvulsant activity but with less seizure prevention compared to the butyl substitution.
对一系列新型喹唑啉 - 4(3H)-酮进行抗惊厥活性评估。以100 mg/kg体重的剂量腹腔注射给白化小鼠后，在小鼠最大电休克（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中检测合成的喹唑啉 - 4(3H)-酮（1 - 24）。采用转棒试验法测定神经毒性。大多数化合物在0.204 - 0.376 mmol/mL的剂量范围内，在scPTZ筛选中表现出抗惊厥活性。在这24种化合物中，化合物8、13和19被证明活性最强，对PTZ诱导的惊厥具有显著保护作用（100%），且活性比乙琥胺强四倍。构效关系得出了有价值的药效团信息，这通过使用靶酶人碳酸酐酶II（HCA II）的分子对接研究得到了证实。所研究的喹唑啉类似物表明，3位的丁基取代对阻止癫痫放电扩散和提高癫痫阈值有显著影响。然而，3位的苄基取代显示出较强的抗惊厥活性，但与丁基取代相比，预防癫痫发作的效果较差。
