Molecular hybrids integrated with Benzofuran, 1,2,3-Triazole and Pyrazole structural motifs: Design, synthesis, biological evaluation, and in vivo studies.

Epilepsy remains a multifactorial neurological disorder, necessitating the development of safer and more effective anti-epileptic agents. In this study, a novel series of benzofuran-triazole-pyrazole hybrids (10a-n) was synthesized and evaluated for anti-convulsant potential using pentylenetetrazole (PTZ)- and pilocarpine (PIL)-induced seizure models in mice. Initial screening identified several active candidates in the PTZ model, with compounds 10a, 10e, and 10n providing complete protection and zero mortality. Subsequent testing in the PIL model confirmed their superior efficacy, evidenced by significant delays in seizure onset, marked reductions in severity, and 100 % survival, surpassing the reference drug valproic acid. Mechanistic studies revealed that these compounds significantly reduced hippocampal oxidative stress (MDA, NO), excitotoxicity (glutamate), pro-inflammatory cytokine levels (TNF-α, IL-6), and glial activation (GFAP, Iba-1), indicating a multimodal neuroprotective profile. Notably, compound 10e exhibited the most pronounced effects across all markers. Safety assessments demonstrated no signs of neurotoxicity, hepatotoxicity, nephrotoxicity, or cardiotoxicity, as evidenced by rotarod performance and serum biomarkers. Collectively, these findings highlight compounds 10a, 10e, and 10n as potent and safe anti-convulsants with promising potential for further preclinical development in the treatment of epilepsy.