Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508
that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus
1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1
) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo
via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1
strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans
longevity-extending assay, compounds 1
significantly extended the survival rates (p
< 0.005 vs.
dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans
model, and compounds 1
exhibited the highest activities (p
< 0.005 vs.
). In the MPP+-induced C57BL/6
mouse PD model, 40 mg/kg of 1
protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p
< 0.001 vs.
MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD.