From molecular design to antiepileptic evaluation: sulfonamide–pyrazole derivatives as promising neuroactive agents

Abstract

Neuroinflammation, oxidative stress, and glutamate-mediated excitotoxicity are central pathological mechanisms underlying epileptogenesis and seizure propagation. In the present study, a series of rationally designed sulfonamide pyrazole derivatives was evaluated for their anticonvulsant potential using pentylenetetrazol (PTZ)- and pilocarpine-induced seizure models in mice. Among the tested compounds, compound 6d emerged as the most promising candidate, exhibiting superior anticonvulsant efficacy. In the PTZ model, compound 6d afforded 90% seizure protection with complete survival, outperforming the reference drug sodium valproate. In the pilocarpine-induced status epilepticus model, compound 6d significantly prolonged seizure onset latency, markedly suppressed seizure severity (reducing Racine scores by >80%), and ensured 100% survival. Mechanistic investigations revealed that compound 6d exerted pronounced neuroprotective effects in hippocampal tissue by significantly attenuating oxidative stress (malondialdehyde and nitrite levels), neuroinflammation (TNF-α and IL-6), and excitotoxicity (glutamate levels), with greater efficacy than valproate. Importantly, sub-chronic oral administration of compound 6d did not induce detectable hepatic, renal, or cardiac toxicity, indicating a favorable preliminary safety profile. Collectively, these findings identify compound 6d as a promising lead anticonvulsant agent with multimodal neuroprotective actions and support its further preclinical development as a potential disease-modifying therapy for epilepsy.