In vivo Anticonvulsant and Neurotoxicity Evaluation and Docking Study of Promising Novel [1,5]-Benzodiazepine Derivatives

El-Gamal, Kamal; El-Morsy, Ahmed; Sherbini, Farag; Elraheim, Adel Saad; Ayaad, Rezek; Saad, Ahmed; Al-Omary, Fatmah; Mansour, Basem

doi:10.21608/dusj.2022.275430

In vivo Anticonvulsant and Neurotoxicity Evaluation and Docking Study of Promising Novel [1,5]-Benzodiazepine Derivatives

Document Type : Original research papers

Authors

10.21608/dusj.2022.275430

Abstract

Background: Benzodiazepines (BDZs) are predominantly prescribed as sedatives, anxiolytics, and anticonvulsants throughout the world and they act on the GABA_A receptor. Objective: New 1,4-BDZ analogues have been designed and synthesized to be evaluated for their anticonvulsant activity. Methods: The newly synthesized compounds have been examined by Maximal electroshock seizure (MES) test, the subcutaneous pentylenetetrazol (scPTZ) seizure test, and rotarod neurotoxicity test. Docking study was performed to justify the activity. Results: The most active compound that showed activity (MES Assay) at both 0.5 h and 4 h at a dose of 30 mg /kg is compound 4b, whereas it has scored protection at a dose level of 100 mg/kg at both 0.5 h and 4 h (scPTZ assay) and did not score any neurotoxicity at maximum dose level unlike phenytoin the reference drug that scored neurotoxicity on mice at dose level of 100 mg/kg. Conclusion: Docking revealed that Compound 4b is active on the three sites of the GABA_A isoform α2β2ɤ. Compared with the reference drug, phenytoin, Compound 4b has more rapid onset and longer duration of action, is more effective, and eventually is safer. Furthermore, we recommend more structural modification studies to come out with much more selective BDZ derivatives to minimize the side effects.

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