Zayed Mohamed F, Ihmaid Saleh K, Ahmed Hany E A, El-Adl Khaled, Asiri Ahmed M, Omar Abdelsattar M
Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah, Al-Munawarah 41477, Saudi Arabia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
Molecules. 2017 Jan 24;22(2):188. doi: 10.3390/molecules22020188.
Some novel fluorinated quinazolines (-) were designed and synthesized to be evaluated for their anticonvulsant activity and their neurotoxicity. Structures of all newly synthesized compounds were confirmed by their infrared (IR), mass spectrometry (MS) spectra, ¹H nuclear magnetic resonance (NMR), C-NMR, and elemental analysis (CHN). The anticonvulsant activity was evaluated by a subcutaneous pentylenetetrazole (scPTZ) test and maximal electroshock (MES)-induced seizure test, while neurotoxicity was evaluated by a rotorod test. The molecular docking was performed for all newly-synthesized compounds to assess their binding affinities to the GABA-A receptor in order to rationalize their anticonvulsant activities in a qualitative way. The data obtained from the molecular modeling was correlated with that obtained from the biological screening. These data showed considerable anticonvulsant activity for all newly-synthesized compounds. Compounds , , and showed the highest binding affinities toward the GABA-A receptor, along with the highest anticonvulsant activities in experimental mice. These compounds also showed low neurotoxicity and low toxicity in the median lethal dose test compared to the reference drugs. A GABA enzymatic assay was performed for these highly active compounds to confirm the obtained results and explain the possible mechanism for anticonvulsant action. The most active compounds might be used as leads for future modification and optimization.
设计并合成了一些新型氟化喹唑啉（-），以评估其抗惊厥活性和神经毒性。所有新合成化合物的结构均通过红外光谱（IR）、质谱（MS）、¹H核磁共振（NMR）、碳核磁共振（C-NMR）和元素分析（CHN）得以确认。通过皮下注射戊四氮（scPTZ）试验和最大电休克（MES）诱导惊厥试验评估抗惊厥活性，同时通过转棒试验评估神经毒性。对所有新合成化合物进行分子对接，以评估它们与GABA-A受体的结合亲和力，从而以定性方式解释其抗惊厥活性。从分子建模获得的数据与从生物学筛选获得的数据相关联。这些数据表明所有新合成化合物均具有相当的抗惊厥活性。化合物 、 和 对GABA-A受体表现出最高的结合亲和力，在实验小鼠中也具有最高的抗惊厥活性。与参考药物相比，这些化合物在半数致死剂量试验中还表现出低神经毒性和低毒性。对这些高活性化合物进行了GABA酶活性测定，以证实所得结果并解释抗惊厥作用的可能机制。最具活性的化合物可能用作未来修饰和优化的先导化合物。
