Unraveling the therapeutic potential of a thiosemicarbazone-based Zn(II) metal-organic triangle complex

Demand for new and effective chemotherapeutic agents continues to drive the search for innovative metal-based drug candidates. We introduce here a metal-organic triangle complex as a novel candidate against breast cancer cells. The self-assembly of a new thiosemicarbazone building block, N⁴-cyclohexyl-2-(2-hydroxy-3,5-diiodobenzylidene)hydrazinecarbothioamide (H₂L), with zinc(II) ions resulted in the formation of a novel metallosupramolecular complex, [Zn₃(µ-L)₃·3DMF] (1), where DMF acts as an ancillary ligand stabilizing the coordination environment. The unique structure of the trinuclear complex, resulting from a rare ONNS bridging coordination, reveals one distorted square pyramidal and two distorted trigonal bipyramidal coordination geometries around the Zn(II) centers. Antibacterial activity of the ligand and its metal complex, assessed initially using agar well diffusion and MIC methods, reveals enhanced efficacy of the triangular complex 1. SEM analysis reveals a bacterial membrane damage mechanism underlying the antibacterial effect, which is consistent with a quantitative protein leakage study. The interactions of H₂L and complex 1 with calf thymus DNA were also found to be very strong, with binding constants of 3.1 × 10⁵ M^-1 and 4.9 × 10⁵ M^-1, respectively. Further, the in vitro cytotoxicity of the ligand and the complex was evaluated against the MCF-7 breast cancer cell line using the MTT assay. Interestingly, complex 1 showed notable inhibition of MCF-7 cell proliferation, with a promising IC₅₀ value of 10.6 µM, outperforming the standard cisplatin (36.66 µM). Further studies suggest that complex 1 is cytotoxic in nature and induces cell death in cancer cell lines by apoptosis, which was further explored via reactive oxygen species (ROS) generation assay. Integrated molecular docking and MD simulations reveal that complex 1 can engage the protein active site through strong and persistent interactions, maintaining conformational stability, which provides theoretical support for its potential anticancer activity.