Substituent and Scaffold Effects on the Antibacterial Activity of Ru(II) Pyridine-Imine Schiff Base Complexes

Abstract

The escalating threat of antimicrobial resistance (AMR) necessitates the development of novel antibacterial agents with alternative mechanisms of action. This study reports the design, synthesis, and biological evaluation of ruthenium(II) complexes derived from pyridine-imine Schiff base ligands featuring systematic aromatic substitutions (–H, –Br, –OH) and two distinct coordination architectures: simple Ru(II) and half-sandwich Ru(II)-p-cymene. The ligands and their corresponding Ru(II) complexes were synthesized in high yields (85–92%) and characterized by melting point, FT-IR, UV-Vis, and ¹H NMR spectroscopy. Spectroscopic data confirmed bidentate N, N′-coordination through the imine and pyridyl nitrogen atoms, evidenced by shifts in C=N stretches (1625–1632 → 1600–1620 cm⁻¹), downfield movement of the imine proton (δ 7.63–7.66 → 7.43–7.55 ppm), and new metal-to-ligand charge transfer (MLCT) bands (363–575 nm). All complexes exhibited enhanced thermal stability (m.p. 175–235 °C) relative to free ligands (70–180 °C). In vitro antibacterial screening against Staphylococcus aureus (Gram-positive) and Escherichia coli (Gram-negative) via disc diffusion revealed that Ru(II) complexes consistently outperformed their parent ligands, with bromo- and hydroxy-substituted p-cymene derivatives (L-C2 and L₁-C2) showing the highest activity, zones of inhibition up to 14–15 mm at 1000 µg/mL. Statistical analysis (two-way ANOVA, p ≤ 0.05), following verification of normality (Shapiro-Wilk) and homogeneity of variance (Levene's test), confirmed significant effects of both substituent type and scaffold architecture on bioactivity. Although none surpassed gentamycin (17–21 mm), the results validate Tweedy's chelation theory and highlight Ru(II) Schiff base complexes as promising scaffolds for antimicrobial development targeting multidrug-resistant pathogens.