Vitamin K-Trolox synergism realized in hybrid neuroprotectant with potent anti-ferroptosi/oxytosis activity, reduced toxicity, and in vivo efficacy in Alzheimer's disease mouse model

In pursuit of developing advanced neuroprotective agents for neurodegenerative disorders, we rationally designed a series of novel hybrid molecules through structural integration of a vitamin K derivative with well-known antioxidants (ferulic acid, melatonin, α-lipoic acid, and Trolox, respectively). Systematic pharmacological evaluation revealed that most hybrids exhibited superior antioxidant activity in both DPPH radical scavenging and ORAC assays. Among these, a Trolox-vitamin K conjugate (compound 16e) emerged as a promising compound, demonstrating exceptional neuroprotective efficacy across multiple neuronal injury models, including oxytosis, ferroptosis, and ATP depletion in HT22 hippocampal neurons. Mechanistic studies confirmed that this compound preserved synergistic cytoprotective effects of its parent pharmacophores against ferroptosis while concurrently exhibiting immunomodulatory activity in microglial cells. Notably, it significantly ameliorated Aβ_25-35-induced cognitive deficits in a murine Alzheimer's disease model at a very low dose (0.1 mg/kg, i.p.), outperforming conventional neuroprotectants in therapeutic potency. These findings position this Trolox/vitamin K hybrid molecule as a neuroprotective candidate with translational potential for treating neurodegenerative pathologies.