title: Synthesis, Modelling, and Anticonvulsant Studies of New Quinazolines Showing Three Highly Active Compounds with Low Toxicity and High Affinity to the GABA-A Receptor.
abstract: Some novel fluorinated quinazolines (5a-j) 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),13C-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. Compounds5b,5c, and5dshowed 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.
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah, Al-Munawarah 41477, Saudi Arabia. mfzayed@taibahu.edu.sa.|Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. mfzayed@taibahu.edu.sa.
authors.forename: Mohamed F
authors.initials: MF
authors.lastname: Zayed
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah, Al-Munawarah 41477, Saudi Arabia. sihmaid@taibahu.edu.sa.
authors.forename: Saleh K
authors.initials: SK
authors.lastname: Ihmaid
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah, Al-Munawarah 41477, Saudi Arabia. heahmad@taibahu.edu.sa.|Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. heahmad@taibahu.edu.sa.
authors.forename: Hany E A
authors.initials: HE
authors.lastname: Ahmed
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. eladlkhaled74@yahoo.com.
authors.forename: Khaled
authors.initials: K
authors.lastname: El-Adl
authors.affiliation: Department of Pharmacognosy and Pharmaceutical Chemistry, College of Pharmacy, Taibah University, Al-Madinah, Al-Munawarah 41477, Saudi Arabia. amasiri@taibahu.edu.sa.
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Asiri
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt. asmansour@kau.edu.sa.|Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia. asmansour@kau.edu.sa.
authors.forename: Abdelsattar M
authors.initials: AM
authors.lastname: Omar
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D011799:Quinazolines; D011963:Receptors, GABA-A
keywords: anticonvulsant; design; epilepsy; neurotoxicity; quinazoline; synthesis