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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. Compounds 5b, 5c, and 5d 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.
Highlights
Epilepsy is a neurological disorder characterized by recurrent seizures [1,2,3,4,5]
Synthesis of 2-amino-5-fluorobenzamide (2) was accomplished by Substituted-6-fluoro-quinazoline-4-amine (5a–j) derivatives were synthesized according to the refluxing of thionylchloride and 2-amino-5-fluorobenzoic acid in benzene, the mixture was methods outlined in Scheme 1
These substituents are joined to the fixed moiety 6-fluroquinazoline
Summary
Epilepsy is a neurological disorder characterized by recurrent seizures [1,2,3,4,5]. It represents a major health problem and inflicts millions of people worldwide [6,7,8,9,10]. This nucleus cancan be substituted on the or the requirement forthe theanticonvulsant anticonvulsant activity It was believed to be valuable to study the effects of two pharmacophoric groups, like previous rationale, it was believed to be valuable to study the effects of two pharmacophoric groups, quinazoline and aromatic amine, in one molecule for anticonvulsant activity. It is a technique in which the substituents are nominated, ordered, and tested based on fluorine atom was selected as a substituent on the quinazoline moiety owing to its safety, small size, low steric interference, and ready availability [12,13].
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