Pyrazolyl–Pyridine Ruthenium Complexes: A New Metallic Line of Defense Against <i>Acinetobacter baumannii</i>

The emergence of antimicrobial resistance (AMR), especially among ESKAPE infections, highlights the pressing necessity for novel chemical frameworks with atypical modes of action. Transition-metal complexes have emerged as attractive possibilities owing to their varied geometries, redox activity, and capacity to interact with biological sites inaccessible to traditional chemical antibiotics. This study presents the antibacterial and antifungal assessment of a series of Ru(II) pyrazolyl-pyridine half-sandwich complexes (C1-C6), thereby broadening the chemical scope of metalloantibiotics previously investigated inside pyridyl-1,2,3-triazolyl frameworks. The compounds were synthesized with good yields and structurally validated by single-crystal X-ray diffraction, demonstrating piano-stool topologies with unique ligand-dependent anion orientations. Extensive biological screening via the Community for Open Antimicrobial Drug Discovery (CO-ADD) platform revealed selective efficacy of complexes C1-C3 against Acinetobacter baumannii, a significant multidrug-resistant pathogen. Cytotoxicity and hemolysis assessments revealed advantageous therapeutic ranges for the most potent combinations. Biophysical investigations, encompassing DNA-binding fluorescence displacement, linear dichroism, and in silico molecular docking and dynamics, elucidated that the lead drug interacts with bacterial DNA via partial intercalation and groove contacts. Collectively, our findings establish Ru(II) pyrazolyl-pyridine complexes as prospective candidates for the advancement of next-generation metalloantibiotics and underscore the significance of coordination-chemistry-driven approaches in addressing AMR.