Bio-Conjugable Thiocarbohydrazone and Thiosemicarbazone Chelators: Synthesis, Redox Properties, and ROS Modulation in Cu(II) Complexes for Targeted Metal-Based Drug Design

The development of metal-based drug candidates demands chelators that combine versatility, biological activity, synthetic accessibility, aqueous solubility, and targeted delivery potential. Thiocarbohydrazones (TCHs)[1] and thiosemicarbazones (TSCs)[2] have garnered attention for their broad-spectrum biological applications and their mixed hard/soft donor system (S, N, O/P), which enables chelation across a wide range of metal ions. However, modern drug discovery requires effective delivery strategies to improve therapeutic efficacy. To address these challenges, we designed a TCH and a TSC displaying a carboxylate moiety. This functional group enhances aqueous solubility of the resulting metal complexes and facilitates conjugation to targeting vectors (e.g., peptides, ubiquitin ligases), enabling site-specific delivery. We evaluated the stability and coordination properties of these chelators with Cu(II), a biologically relevant metal ion. To assess their redox behavior and interactions with reactive oxygen species (ROS), we conducted a series of experiments[3,4]: • Stability assays in the presence of excess H₂O₂ and hydroxyl radicals (•OH), as well as under increasing concentrations of KO₂ (a source of superoxide, O₂⁻). • DPPH radical scavenging assays to quantify the antioxidant capacity of the free chelators and their Cu(II) complexes. • SOD-like activity through McCord and Fridovich assays. Our findings demonstrate that these tunable and bio-conjugable platforms hold promise for the development of targeted metal-based therapeutics.