Unveiling anxiolytic and anticonvulsant potential of ibuprofen acylhydrazones: a combined synthesis, quantum chemical calculations, molecular docking and in vivo study in adult zebrafish

Abstract Anxiety is characterized by persistent feelings of apprehension, worry and fear, which can lead to a significant reduction in quality of life and the development of other mental health conditions, such as depression. In this study, we investigated the effects of ibuprofen derivatives on anxiolytic and anticonvulsant behavior in an adult zebrafish model. In this study, we designed, synthesized and biologically evaluated new ibuprofen-derived acylhydrazones, integrating chemical synthesis, quantum chemical calculations, molecular docking and in vivo assays in adult zebrafish (Danio rerio). The results demonstrated that ibuprofen was converted to its hydrazide and subsequently condensed with 4-chlorobenzaldehyde to obtain the chlorinated acylhydrazone (HDZI IBU Cl), with structures confirmed by 1 H and 13 C NMR spectroscopy. Density Functional Theory calculations revealed a HOMO–LUMO gap of 4.405 eV (vacuum) and increased electrophilicity in polar media, indicating favorable electronic stability. In vivo, both hydrazide and HDZI IBU Cl (0.1-1.0 mg/mL) showed no acute toxicity (LC₅₀ > 1.0 mg/mL). In the light/dark test, both compounds significantly increased time spent in the light zone, indicating anxiolytic-like effects. In the PTZ-induced seizure model, HDZI IBU Cl (0.5 mg/mL) significantly delayed seizure stages. Flumazenil reversed the anticonvulsant effect, suggesting GABAA receptor involvement. Docking studies showed stable binding (RMSD < 2 Å) and favourable binding energies (− 7.5 to − 9.5 kcal/mol), comparable to reference ligands E2J, CWD, FLX. In 5-HT2C and 5-HT3A receptors, HDZI IBU Cl interacted mainly through hydrophobic contacts with key active-site residues, sharing similarities with co-crystallized inhibitors. For GABAA, it exhibited strong affinity (− 8.9 kcal/mol) and interactions like diazepam, including hydrophobic, hydrogen bond, and π-cation interactions, suggesting a comparable modulatory mechanism. These results provide a promising basis for the development of new anticonvulsants and anxiolytics based on ibuprofen derivatives, highlighting the importance of structural modifications in optimizing therapeutic efficacy and minimizing cognitive side effects.