Antimicrobial Properties of Tris(homoleptic) Ruthenium(II) 2‑Pyridyl-1,2,3-triazole “Click” Complexes against Pathogenic Bacteria, Including Methicillin-Resistant Staphylococcus aureus (MRSA)

A series of tris­(homoleptic) ruthenium­(II) complexes of 2-(1-<b>R</b>-1<i>H</i>-1,2,3-triazol-4-yl)­pyridine “click” ligands (<b>R-pytri</b>) with various aliphatic (R = butyl, hexyl, octyl, dodecyl, and hexdecyl) and aromatic (R = phenyl and benzyl) substituents was synthesized in good yields (52%–66%). The [Ru­(<b>R-pytri</b>)₃]²⁺(X^–)₂ complexes (where X^– = PF₆^– or Cl^–) were characterized by elemental analysis, high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), ¹H and ¹³C nuclear magnetic resonance (NMR) and infrared (IR) spectroscopies, and the molecular structures of six of the compounds confirmed by X-ray crystallography. ¹H NMR analysis showed that the as-synthesized materials were a statistical mixture of the <i>mer</i>- and <i>fac</i>-[Ru­(<b>R-pytri</b>)₃]²⁺ complexes. These diastereomers were separated using column chromatography. The electronic structures of the <i>mer</i>- and <i>fac</i>-[Ru­(<b>R-pytri</b>)₃]²⁺ complexes were examined using ultraviolet–visible (UV-Vis) spectroscopy and cyclic and differential pulse voltammetry. The family of <b>R-pytri</b> ligands and the corresponding <i>mer</i>- and <i>fac</i>-[Ru­(<b>R-pytri</b>)₃]²⁺ complexes were tested for antimicrobial activity <i>in vitro</i> against both Staphylococcus aureus and Escherichia coli bacteria. Agar-based disk diffusion assays indicated that two of the [Ru­(<b>R-pytri</b>)₃]­(X)₂ complexes (where X = PF₆^– and R = hexyl or octyl) displayed good antimicrobial activity against Gram-positive S. aureus and no activity against Gram-negative E. coli at the concentrations tested. The most active [Ru­(<b>R-pytri</b>)₃]²⁺ complexes ([Ru­(<b>hexpytri</b>)₃]²⁺ and Ru­(<b>octpytri</b>)₃]²⁺) were converted to the water-soluble chloride salts and screened for their activity against a wider range of pathogenic bacteria. As with the preliminary screen, the complexes showed good activity against a variety of Gram-positive strains (minimum inhibitory concentration (MIC) = 1–8 μg/mL) but were less effective against Gram-negative bacteria (MIC = 16–128 μg/mL). Most interestingly, in some cases, the ruthenium­(II) “click” complexes proved more active (MIC = 4–8 μg/mL) than the gentamicin control (MIC = 16 μg/mL) against two strains of methicillin-resistant S. aureus (MRSA) (MR 4393 and MR 4549). Transmission electron microscopy (TEM) experiments and propidium iodide assays suggested that the main mode of action for the ruthenium­(II) <b>R-pytri</b> complexes was cell wall/cytoplasmic membrane disruption. Cytotoxicity experiments on human dermal keratinocyte and Vero (African green monkey kidney epithelial) cell lines suggested that the complexes were only modestly cytotoxic at concentrations well above the MIC values

[Re(CO)₃]⁺ Complexes of <i>exo</i>-Functionalized Tridentate “Click” Macrocycles: Synthesis, Stability, Photophysical Properties, Bioconjugation, and Antibacterial Activity

There is considerable interest in the development of bifunctional ligand scaffolds for the group 7 metals due to potential biological applications. Building on our recent work in the development of “click” ligands and macrocycles, we show that a CuAAC “click” approach can be exploited for the synthesis of a small family of bioconjugated tridentate pyridyl-1,2,3-triazole macrocycles. These bioconjugated tridentate macrocycles form stable [Re­(CO)₃]⁺ complexes, and this could facilitate the development of [M­(CO)₃]⁺ (M = Mn, Tc, Re) targeted agents. The parent macrocycle, bioconjugates, and [Re­(CO)₃]⁺ complexes were characterized by elemental analysis and HR-ESI-MS, ¹H and ¹³C NMR, and IR spectroscopy, and the molecular structures of the alcohol-functionalized macrocycle and two of the Re­(I) complexes were confirmed by X-ray crystallography. The electronic structure of the parent [Re­(CO)₃]⁺ macrocycle complex was examined using UV–vis, Raman, and emission spectroscopy and density functional theory calculations. The complex exhibited intense absorptions in the UV region which were modeled using time-dependent density functional theory (TD-DFT). The calculations suggest that the lower energy part of the absorption band is MLCT in nature and additional higher energy π–π* transitions are present. The complex was weakly emissive at room temperature in methanol with a quantum yield of 5.1 × 10^–3 and correspondingly short excited state lifetime (τ ≈ 20 ns). The family of macrocycles and the corresponding Re­(I) complexes were tested for antimicrobial activity <i>in vitro</i> against both Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli) microorganisms. Agar-based disk diffusion assays indicated that two of the Re­(I) complexes displayed antimicrobial activity but the minimum inhibitory concentrations (MIC) for these compounds proved to be extremely modest (MIC > 256 μg/mL)