Sun_2025_Chem.Biodivers__e01827

Considerable evidence suggests that metal ions play crucial roles in Alzheimer's disease (AD) progression, spurring the development of metal-involved therapeutic strategies. In this study, biochanin A, a bioactive ingredient derived fromTrifolium pratense L. (a traditional Chinese medicine [TCM]), was identified as a lead compound for the rational design of multifunctional metal chelators. A series of biochanin A derivatives (compounds a-e) was synthesized through a one-step carbamate introduction reaction. Their drug-likeness and pharmacokinetic profiles were assessed using an online prediction server. The bioactivities, including metal ion chelation, beta-amyloid aggregation regulation, reactive oxygen species elimination, cholinesterase inhibition, and neurocytotoxicity were evaluated. The results indicated that compounds (a-e) possessed favorable pharmacokinetic profiles and potential as multifunctional metal chelators with minimal neurocytotoxicity, with compound d emerging as a particularly promising candidate. These findings may provide meaningful information for developing novel multifunctional metal chelators for AD treatment and innovative drugs derived from TCM.