Design, Docking, Synthesis, and Biological Evaluation of Pyrazolone Derivatives as Potential Dual-Action Antimicrobial and Antiepileptic Agents

<b>Background/Objectives:</b> Epilepsy is characterized by unpredictable seizures and drug resistance, along with rising antimicrobial resistance (AMR), highlighting the urgent need for innovative dual-action therapies. This study aimed to design, develop, and evaluate novel pyrazolone derivatives for a dual antimicrobial and antiepileptic potential. <b>Methods:</b> Novel pyrazolone derivatives were designed, synthesized (using 2,4-dinitrophenylhydrazine/semicarbazide condensation with ethyl acetoacetate), and evaluated through molecular docking against antimicrobial (4URM, 3FYV, 3FRA) and neuronal targets (4COF, 5TP9, 5L1F). The in vitro antimicrobial activity was assessed against Gram-positive (<i>S. aureus</i>) and in vitro Gram-negative (<i>E. coli</i>, <i>P. aeruginosa</i>) strains via agar cup plate assays, while in vivo antiepileptic efficacy was tested in a PTZ-induced seizure model in Swiss albino mice. <b>Results:</b> Compound IIa showed potent dual activity, inhibiting <i>E. coli</i> (9 mm zone at 80 μg/mL) and <i>S. aureus</i> (9.5 mm at 80 μg/mL), alongside a significantly delayed seizure onset in the PTZ-induced mouse model (100% survival rate, 45 sec delayed seizure onset, <i>p</i> < 0.001). Compounds Ia and Id showed selective activity against <i>E. coli</i> (6 mm at 80 μg/mL) and P. aeruginosa (7 mm at 80 μg/mL), respectively. Docking studies revealed that compound IIa has a superior binding affinity (-7.57 kcal/mol for 3FYV) compared to standards, driven by hydrogen bonds (SER X: 49) and hydrophobic interactions (LEU X: 20). <b>Conclusions:</b> This study presents a novel approach by proposing a rationally designed pyrazolone scaffold exhibiting both antimicrobial and antiepileptic activity, which integrates in silico modeling with experimental validation. Compound IIa emerged with preliminary dual biological activities, exhibiting strong antibacterial activity, a superior binding affinity toward both bacterial and neuronal targets, and notable seizure prevention in vivo. These findings show the potential of multifunctional pyrazolone derivatives as a new treatment strategy for addressing drug-resistant infections linked to epilepsy and support further optimization toward clinical development.