Cyclometalated Palladium Complexes as Promising Anti-Mycobacterial Agents: Synthesis, Biological Evaluation, and Mechanism Characterization

Abstract

Tuberculosis remains a grave threat to global public health, and the development of novel and effective therapeutic agents against mycobacterial infections is an urgent priority. Herein, we developed a series of cyclometalated palladium(II) complexes with 2-aminobiphenyl that exhibit antibacterial activities and fully characterized by 1H NMR, ESI-MS, FT-IR, ICP-OES and elemental analysis. All synthesized complexes exhibited potent in vitro antimycobacterial activity with MICs as low as 1.25 μM. Importantly, these complexes exhibit minimal cytotoxicity, robust stability, prominent cell-penetrating bactericidal potency and low propensity to induce drug resistance. Mechanism-of-action study demonstrated that their favorable antimycobacterial activity may be achieved by targeting the transporter MmpL11 and intracellular ROS accumulation. Molecular docking simulations confirmed that cyclometalated palladium complexes inhibit MmpL11 via multiple interaction effect, suggesting MmpL11 is a potential target for developing drug-resistant mycobacterial inhibitors. Taken together, our study identifies cyclometalated palladium complexes as potential compounds with potent antimycobacterial agents.