DESIGN-DRIVEN DISCOVERY OF 3,5-DISUBSTITUTED HYDANTOIN-BASED ANTICONVULSANTS SUPPORTED BY IN VIVO AND IN SILICO STUDIES

Objectives: The present study aimed to synthesize a series of imidazolidine-2,4-dione (hydantoin) derivatives 5a–5g containing an indole moiety and to evaluate their anticonvulsant potential both in vivo and in silico. The study further sought to explore structure–activity relationships and predict the binding interactions of these compounds with the voltage-gated sodium channel protein (PDB ID: 3RVY). Methods: The target compounds 5a–5g were synthesized using standard synthetic methodologies and characterized through physical and spectral analyses. Wistar albino rats were used to assess the in vivo anticonvulsant activity employing maximal electroshock (MES) and pentylenetetrazole (PTZ) seizure models, with phenytoin serving as the reference drug. In addition, molecular docking studies were performed using AutoDockVina to evaluate the binding affinities of the synthesized compounds at the sodium channel active site. Results: All synthesized compounds were obtained in good yields and confirmed through spectral analyses. In vivo testing showed that compounds 5c and 5d exhibited the highest percent protection in the PTZ (5c: 83.33%, 5d: 66.66%) and MES (5c: 83.33%, 5d: 83.33%) models. Molecular docking results revealed strong predicted binding affinities for compound 5b (–9.5 kcal/mol) and compounds 5c and 5d (–9.1 kcal/mol each) at the sodium channel target, which were comparable to or better than the reference ligand phenytoin. Conclusion: Both in vivo anticonvulsant activity and in silico molecular docking studies indicated that electron-withdrawing nitro-substituted compounds, particularly 5c and 5d, possess significant anticonvulsant potential and strong binding affinity at the sodium channel active site. These findings highlight the promise of nitro-substituted hydantoin derivatives as lead compounds for further pharmacological optimization and development as anticonvulsant agents.