Design, synthesis, and in vivo antiepileptic evaluation of novel quinazolinone-phthalimide derivatives

Epilepsy impacts millions of individuals globally, with around one-third of patients not responding to existing antiepileptic medications. As a result, in the current study, quinazolinone-phthalimide derivatives were designed, synthesized, and characterized by 1H NMR, 13C NMR, FTIR, and Mass spectrometry. To assess antiepileptic activity, two different animal seizure models pentylenetetrazole and lithium-pilocarpine-induced seizure models were employed. The results indicated that the efficacy of compounds 8j and 8k, in terms of latency and seizure count, was comparable to that of diazepam, with no observed mortality, suggesting a favorable safety profile. Also, antagonistic activity on the GABAA receptor was confirmed in an animal model in the presence of flumazenil. Docking studies also showed that both compounds interact with key residues in the benzodiazepine-binding pocket and penetrate deeper into the GABAA receptor binding site. Molecular dynamics confirmed the stability of complexes. Thus, quinazolinone-phthalimide derivatives emerge as promising candidates for further development and investigation as antiepileptic agents.