Pyrazole carboxylic acid borneol esters: Novel neuroprotective agents with rapid, efficient brain penetration for the treatment of ischemic stroke

Ischemic stroke (IS) is an acute cerebrovascular condition marked by a high incidence, disability rate, and mortality. Edaravone and Dexborneol Concentrated Injection Solution (EDB) has been approved to improve neurological symptoms, daily living activities, and functional impairments resulting from acute IS. Our previous studies showed that replacing the benzene ring of Edaravone (Eda) with pyridine enhances its free radical scavenging capacity. In this study, we further oxidized the methyl group of Eda to a carboxylic acid and used a structural hybridization strategy with (+)-borneol to synthesize a series of pyrazole carboxylic acid borneol esters. We evaluated the free radical scavenging ability of the synthesized compounds, identifying candidate compound B16, which outperforms Eda. The IC₅₀ values of B16 against DPPH and ABTS free radicals were 7.98 μM and 5.50 μM, respectively. Cellular studies have shown that B16 maintains intracellular redox homeostasis and mitochondrial function, while also alleviating DNA damage in an oxygen - glucose deprivation/reperfusion (OGD/R)-induced SH-SY5Y cell model, demonstrating excellent neuroprotective effects. Further in vivo pharmacodynamic studies have demonstrated that B16 not only restores cerebral blood flow and significantly reduces infarct size in middle cerebral artery occlusion/reperfusion (MCAO/R) mice, but also improves sensory and motor functions, and promotes the recovery of neuronal cells and the blood-brain barrier (BBB) in the brain. Notably, B16 exhibits excellent BBB permeability and shows promising brain exposure levels within 5 min of administration. Preliminary biosafety studies indicated no obvious organ toxicity from B16. Collectively, the pyrazole carboxylic acid borneol ester compound B16 holds promise as a candidate for anti-IS treatment.

BBB permeability; Ischemic stroke; Pyrazole carboxylic acid; Radical scavenging.