Metal-based chemotherapeutics have long been dominated by platinum drugs such as cisplatin, carboplatin, and oxaliplatin, which have firmly established metal coordination complexes as a cornerstone of chemotherapeutic regimens. However, their clinical utility is constrained by dose-limiting toxicity, acquired resistance, and poor selectivity toward malignant cells over healthy tissues. To address these problems, researchers are exploring metal complexes other than platinum that can be used innovatively to target distinct biological pathways with different methods. Ru, Cu, and Bi have an emerging role in this objective. Sometimes they work through mitochondrial, redox, or protein-targeting pathways that are different from the manner in which Pt drugs crosslink with DNA. The demand for novel approaches that can overcome resistance and reduce systemic toxicity has been emphasized by the fact that lung cancer remains a major cause of cancer mortality globally [[1], [2], [3]].

Bi(III) represents a promising yet comparatively less explored metal ion in medicinal inorganic chemistry. Due to its closed-shell 6s2 configuration, Bi(III) is relatively resistant to redox changes under physiological conditions and in assay conditions, offering enhanced thermodynamic stability compared to many transition metals. Additional evidence of a positive safety profile in humans comes from clinically applied bismuth formulations, such as ranitidine bismuth citrate (Tritec®/Pylorid®), bismuth subcitrate (De-Nol®), and bismuth subsalicylate (Pepto-Bismol®) [4]. The emerging therapeutic promise of Bi-based drugs on anticancer, antibacterial, and antiparasitic fronts has been highlighted by recent reviews [3,5,6]. Complementary assessments emphasize that ligand design and derived geometries (trigonal, tetrahedral, and octahedral) significantly influence bioactivity in homoleptic Bi(III) complexes [7].

Dithiocarbamates (DTCs, R2NCS2−) are soft, sulfur-donor ligands that stabilize soft metal centers through κ2(S, S) chelation and enable electronic/steric tuning via thioureide resonance and substituent design [8]. Beyond their extensive use in catalysis and materials, metal-DTC complexes are increasingly explored in bioinorganic chemistry, including applications in anticancer, antimicrobial, and antioxidant treatments [[9], [10], [11]]. For platinum therapeutics, Pt(II)DTC complexes can surpass cisplatin in potency, with mechanisms that involve the generation of reactive oxygen species (ROS) or the inhibition of the NF-кB pathway [12,13]. In parallel, copper DTC systems are being re-appraised for their ability to perturb copper homeostasis and trigger apoptosis in drug-resistant cancers [14]. These observations validate DTCs as biologically active chelators; when combined with Homoleptic Bi(III) complexes, they yield a hybrid platform that couples Bi-centered stability with sulfur-ligand-mediated bioactivity.

Previous reports have highlighted that Bi(III) complexes with asymmetric NN'O ligands exhibit cytotoxicity (IC50 0.3–0.4 μM) against chronic myelogenous leukemia cells and display antibacterial properties [15]. Similarly, the in vitro cytotoxic potential of simple Bi-DTC frameworks has been demonstrated across multiple tumor lines [16]. To advance this field, the development of Bi-DTC frameworks that allow for a direct correlation between electronic structure, coordination geometry, and cytotoxic behaviour within a coherent Bi(III) system [17] is necessary.

A less explored dimension in therapeutic metal design is positional isomerism within the ligand framework. Hydroxy substituent at the ortho, meta, or para positions can modulate intramolecular hydrogen bonding, steric accessibility, lipophilicity, and π-electron delocalization, thereby influencing BiS bond metrics, coordination geometry, ligand-field strength, and ultimately cellular uptakeprotein. Mechanistically, increased reactive oxygen species (ROS) generation and mitochondrial membrane depolarization reflect oxidative stress–associated, non-DNA-targeting pathways of cytotoxicity. Such mechanisms may help circumvent traditional resistance associated with DNA-directed agents and potentially reduce genotoxic side effects, an approach increasingly explored in the development of next-generation metallodrugs. [3,[18], [19], [20]].

Herein, we report a systematic series of homoleptic Bi(III) dithiocarbamate positional isomers, Bi-2ba, Bi-3ba, and Bi-4ba. These complexes are synthesized and fully characterized (IR, 1H/ 13C NMR, and UV–vis, HRMS) to establish purity, types of electronic transitions, and bonding patterns. Supportive DFT and frontier molecular orbital (FMO) analyses reveal comparable but meaningful variations in HOMO-LUMO gaps among the isomers, with Bi-4ba exhibiting the narrower separation, consistent with intra-ligand charge transfer and redox cycling. Biological evaluation in A549 lung carcinoma cells demonstrates a clear isomer dependent potency trend (Bi-4ba > Bi-3ba > Bi-2ba), correlating with increased ROS generation and mitochondrial dysfunction. Collectively, these findings establish positional isomerism as a rational design parameter that links electronic structure to redox-mediated cytotoxicity in Bi(III)-dithiocarbamate complexes.