Design and Development of Sulfonamide-Chalcones as Antiepileptic Candidates: Computational and Zebrafish-Based...

The study aims to develop safer and more effective antiepileptic drugs (AEDs) by targeting the γ-aminobutyric acid type A (GABA_A) receptor, an important inhibitory neurotransmitter system involved in the control of neuronal excitability and seizures. With epilepsy rates rising worldwide and current AEDs often causing serious side effects, new neurotherapeutics with better efficacy and safety are urgently needed. In this context, sulfonamides, known for their proven anticonvulsant properties, were selected as the core scaffold for the development of new sulfonamide-chalcone hybrids (compounds 1-36) as potential AED candidates. These compounds were analyzed for their drug-likeness, ADMET profiles, and electronic properties using density functional theory (DFT) calculations. Molecular docking studies were then performed to examine their binding affinity to the GABA_A receptor, revealing that the 4-(trifluoromethyl)-sulfonamide-chalcones (19, 20, and 21) had the highest binding affinity (-10.3 to -10.1 kcal/mol) compared to the standard AED, valproic acid (VPA; -5.4 kcal/mol). To further support these findings, molecular dynamics (MD) simulations were performed with the top candidates. Analyses of root-mean-square deviation (RMSD), hydrogen bonding (H-bonds), radius of gyration (R _g), and solvent-accessible surface area (SASA) indicated that compound 20 exhibited the greatest stability throughout the simulation. Subsequently, to address toxicity risks, in vivo zebrafish mortality assays were performed to determine the LC₅₀ values before proceeding to behavioral testing. All compounds showed a favorable safety profile and antiepileptic potential, as validated using a pentylenetetrazole (PTZ)-induced seizure zebrafish model. In conclusion, this integrated computational-experimental approach highlights the therapeutic potential of sulfonamide-chalcone hybrids, particularly 4-(trifluoromethyl)-N-(4-(3-(4-(trifluoromethyl)-phenyl)-acryloyl)-phenyl)-benzenesulfonamide (compound 20), as potential positive allosteric modulators of the GABA_A receptor, offering a viable pathway for the development of next-generation AEDs with improved efficacy and safety profiles.