Discovery of a glycosylated colchicine derivative as a neuroprotective agent for ischemic stroke

Ischemic stroke, a leading cause of mortality, arises from blocked brain blood flow that rapidly injures neurons, and repeated failures of neuroprotective molecule trials highlight the complexity of developing effective therapies. Colchicine is a well-known anti-inflammatory agent that modulates microtubule dynamics and suppresses inflammatory cascades in ischemic stroke, but its clinical use is limited by toxicity and narrow therapeutic windows. To meet these challenges, we report the design, synthesis, and evaluation of glyco-conjugated 4H-benzo[3,4]cyclohepta[1,2-b]furan-4-one derivative (116B), structurally inspired by colchicine while introducing new structural moieties optimized via pharmacophore-based modelling aimed at improving safety and enhancing neuroprotective activity. An efficient convergent synthesis featuring intramolecular Friedel-Crafts acylation and glycosylation as a key step was rigorously optimized, offering 116B in high yield. In the current study, 116B mitigated H₂O₂ induced oxidative stress in SH-SY5Y neuronal cells by reducing ROS, restoring mitochondrial function, and inhibiting MAPK-driven inflammation (p < .001) in vitro. The in vivo results demonstrated profound efficacy in fostering neuronal survival and post-stroke functional recovery where 116B (5 mg/kg) outperformed aspirin in a rat tBCCAO/R model by reducing the infarct volume by 30 % and improving neurological scores (p < .0001). It also decreased microglia and astrocyte activation in the cortex and striatum, alongside increased SOD1, CAT, and GPx4 enzyme activities in these regions. 116B exhibited 86 % serum stability and crossed the blood-brain barrier, supporting its therapeutic potential. These findings identify 116B as a promising neuroprotective agent with novel design and enhanced therapeutic potential for stroke treatment.

Brain infarct; Glia activation; Glycosylated 4H-benzo [3,4] cyclohepta [1,2-b] furan-4-one; Ischemic stroke; Mitochondrial damage; Neuronal apoptosis; Oxidative stress.