The authors report synthesis of chiral Co/Zn Schiff-base clusters (R/S-Co4Zn5L10 and related Co complexes) and show that R-enantiomers rescue dopaminergic neuron loss, improve dopamine-dependent locomotion, and inhibit α-synuclein aggregation in nematode Parkinson’s models.

Demonstrates mechanism-relevant (α‑synuclein aggregation inhibition) in vivo neuroprotective activity for a novel metal-based compound class, making it a promising early-stage lead for follow-up in mammalian models despite toxicity and translational uncertainties.

Hierarchical chiral structures have wide applications in materials science and biomedicine. The synthesis of multilevel chiral structures with specific functions is a key issue. In this work, we have successfully designed and synthesized R/S-Co4Zn5L10 (L = C16H15O3N) quinary chiral helix, in which the chirality transfers from the chiral carbon atoms of ligands to octahedral stereochirality, then to a single helix, further to a supramolecular helical chain, and ultimately to the chiral crystal structure. R/S-Co4Zn5L10 consists of two chiral building units, R/S-Zn3L2 and R/S-CoL2. R/S-CoL2 can also agglomerate into R/S-Co4L6. The evaluation of the biocompatibility and bioactivity for three pairs of enantiomers reveals that R-Co4Zn5L10 and R-CoL2 effectively restore dopaminergic neuron loss and improve dopamine-dependent locomotion deficits in nematodes. Additionally, these compounds inhibit α-synuclein aggregation during nematode development. These findings suggest that elaborately designed cobalt-based chiral structures have potential as novel therapeutic candidates for Parkinson's disease.