Phenoxyacetic acid scaffold as a platform for dual anticonvulsant and anti-inflammatory drug design

Abstract

Neuroinflammation is increasingly recognized as a critical contributor to epileptogenesis and antiepileptic drug resistance, emphasizing the need for multi-target therapeutic strategies. In the present study, a series of phenoxyacetic acid-based hydrazone derivatives were rationally designed and synthesized as dual anti-inflammatory and antiepileptic agents through positional modification of the phenoxyacetic acid scaffold followed by hydrazone formation with diverse hydrazides. The synthesized compounds were spectroscopically characterized and evaluated using an integrated in silico, in vitro, and in vivo workflow. ADME and ProTox-3.0 predictions suggested favorable drug-likeness and low acute oral toxicity, while molecular docking indicated that the lead compound 7b established stable interactions with voltage-gated calcium channels and cyclooxygenase-2, exhibiting binding modes comparable to sodium valproate and celecoxib, respectively. Biologically, compound 7b emerged as the most active derivative, demonstrating potent anti-inflammatory activity in the carrageenan-induced paw edema model with 55.38% early inhibition and sustained suppression of 49.15% at 5 h, together with the lowest paw weight increase (21.28%), representing a 59.25% reduction versus the carrageenan group. This effect correlated with marked downregulation of tumor necrosis factor (TNF-α) and prostaglandin E₂ (PGE₂), supporting effective modulation of inflammatory signaling. Compound 7b also exhibited strong analgesic activity, increasing nociceptive latency by 37.76% at 30 min and reaching 52.08% at 120 min in the hot-plate assay. Remarkable anticonvulsant efficacy was observed in both the pentylenetetrazole (PTZ) induced seizure model and pilocarpine-induced seizure model, where 7b afforded 90% seizure protection with complete prevention of mortality, delayed seizure onset by 156.43%, reduced seizure severity by 70.53%, and achieved 100% survival, surpassing sodium valproate. Mechanistically, 7b markedly attenuated hippocampal neuroinflammation and excitotoxicity, reducing TNF-α, IL-6, and glutamate levels while suppressing glial activation markers glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1, confirming pronounced neuroprotective and anti-neuroinflammatory effects.