Design, Synthesis, and Evaluation of Voltage-gated Sodium Channel Inhibitors as Anticonvulsant Agents

Introduction: The objective of this study is to explore the therapeutic potential of synthesized hetero fused acylurea derivatives by investigating their ability to bind with voltagegated sodium ion channel receptors, followed by anticonvulsant evaluation. Methods: The research involves synthesizing a series of hetero-fused acylurea compounds (4a-f, 5a-f) and evaluating their anticonvulsant potential. The Cresset Flare software was used for in silico testing against the voltage-gated sodium ion channel receptor (PDB ID: 6SXC). Maximal Electroshock Seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) models were used for in vivo testing. The compounds were further assessed using the online SwissADME and Protein Plus software. Results: All the compounds exhibited good binding affinity with the selected receptor, with energies ranging from -3.915 to -5.683 kcal/mol. 3-Amino-N-(4-hydroxy-3-methoxybenzoyl) pyrazine-1(2H)-carboxamide (4f) has shown hydrogen bonding for aaLYS A226 (binding affinity of -5.683 kcal/mole) with a bond length of 2.6 Å and was comparable to the standard drug phenytoin (-5.683 kcal/mole). In vivo, study results of the compounds showed an optimum percentage protection range of 34 to 60% against epileptic seizures, compared to 59% protection afforded by phenytoin. Discussion: The synthesized acylurea derivatives demonstrated good sodium-channel binding and moderate to strong anticonvulsant activity. Compound 4f showed the best interaction, comparable to phenytoin, which aligned with its in vivo protection. Overall, the consistent in silico and in vivo results indicate that these molecules, especially 4f, hold promise as lead anticonvulsant candidates. Conclusion: All the synthesized acylurea derivatives possess comparable activity to the standard drug. Thus, it can be concluded that the synthesized analogs are potential candidates for further investigation.