Metal coordination of thiazole-benzothiazole derivatives improves the antiproliferative efficacy against various human cancer cells: Synthesis, X-ray structures and in silico studies.

We designed and synthesized a series of coordination environments with variation in bioinorganic element, spatial configuration, molecular size, charge distribution, and flexibility to evaluate their influence on oncogenic bioprocess through modulation of molecular interaction and bioactivity. A hybrid molecule of thiazole-benzothiazole core (TbtH) with N3S2 donor sites has been reacted with metal (ZnII, NiII, and CdII) salts to produce both neutral (inner metallic) and ionic complexes. The ligand (TbtH) has a planar structure and forms distorted octahedral complexes (C1-C5) as ascertained by X-ray crystallography. Electron delocalisation in different frontier molecular orbitals (FMOs) reveals the electronic transition sequence as C2, C4 > C5 > C1 > C3. The order suggests the innermetallic C2 and C4 are soft metal complexes and especially demonstrate superior biological activity. The compounds demonstrated potent cytotoxicity in a dose-dependent manner, indicating a favorable and selective antitumor activity against various human cancer cells, viz., breast cancer (MDA-MB-231 and MCF-7), lung cancer (A549), and liver cancer (HepG2). Among the compounds, C2 demonstrates robust and selective cytotoxicity across cancer cell models and has emerged as the lead cytotoxic agent against triple-negative breast cancer cells with the IC50 value of 9.46 ± 0.48 μM. The concurrence of mitochondrial depolarisation and caspase-3 activation elucidates a programmed cell death mechanistic cascade inducing intrinsic apoptosis in MDA-MB-231 cells through mitochondrial dysfunction and downstream caspase engagement. Besides the C2 also inhibits Topoisomerase II activity in a dose-dependent manner as envisaged by the kDNA decatenation assay. Molecular docking and molecular dynamics studies corroborated the experimental findings, identifying C2 as the most suitable candidate for MDA-MB-231 cells with the highest binding free energy (-7.41 kcal/mol). RMSD and RMSF analyses also confirm that both the protein and substrate remain stable within the binding pocket, with minimal structural fluctuations. Overall, C2 demonstrates superior stability, binding affinity, and cytotoxic potential, making it the most promising candidate among the reported compounds.