Discovery and characterization of phenoxyacetic acid derivatives as potential antiepileptic agents

Abstract

This study aimed to discover novel multifunctional anticonvulsant agents through the evaluation of a series of test compounds 5d-f, 7b, and 10c-f, which were previously identified based on their potent anti-inflammatory activity in both <i>in vitro</i> and <i>in vivo</i> models in acute and chronic seizure models. Initial screening in the pentylenetetrazol (PTZ)-induced seizure model identified compounds 7b, 5f, 5e, and 10c as the most effective, with compound 7b demonstrating complete seizure protection (100%) and zero mortality, outperforming the reference drug valproic acid (VI). These four candidates were further assessed in the pilocarpine-induced temporal lobe epilepsy model. Compound 7b again showed superior efficacy, significantly delaying seizure onset by 188.6%, reducing seizure severity at all time points, and ensuring 100% survival. Mechanistic studies revealed that 7b markedly reduced hippocampal oxidative stress markers, including malondialdehyde by 67.2% and nitric oxide levels by 41.0%. It also suppressed the neuroinflammatory cytokines TNF-α and IL-6 by 56.9% and 63.0%, respectively. In addition, compound 7b attenuated excitotoxic glutamate accumulation by 61.5% and downregulated glial activation markers GFAP and Iba-1 by 73.9% and 49.8%, respectively, consistently outperforming valproic acid. Importantly, safety evaluation confirmed that high-dose administration of 7b did not induce hepatic, renal, or cardiac toxicity. Collectively, these findings establish compound 7b as a potent, safe, and multifunction anti-inflammatory and antiepileptic candidate, warranting further pharmacological and mechanistic investigation.