Mononuclear Polypyridylruthenium(II) Complexes with High Membrane Permeability in Gram‐Negative Bacteria—in particular Pseudomonas aeruginosa

Ruthenium(II) complexes containing the tetradentate ligand bis[4(4′‐methyl‐2,2′‐bipyridyl)]‐1,n‐alkane (“bb_n”; n=10 and 12) have been synthesised and their geometric isomers separated. All [Ru(phen)(bb_n)]²⁺ (phen=1,10‐phenanthroline) complexes exhibited excellent activity against Gram‐positive bacteria, but only the cis‐α‐[Ru(phen)(bb₁₂)]²⁺ species showed good activity against Gram‐negative species. In particular, the cis‐α‐[Ru(phen)(bb₁₂)]²⁺ complex was two to four times more active than the cis‐β‐[Ru(phen)(bb₁₂)]²⁺ complex against the Gram‐negative strains. The cis‐α‐ and cis‐β‐[Ru(phen)(bb₁₂)]²⁺ complexes readily accumulated in the bacteria but, significantly, showed the highest level of uptake in Pseudomonas aeruginosa. Furthermore, the accumulation of the cis‐α‐ and cis‐β‐[Ru(phen)(bb₁₂)]²⁺ complexes in P. aeruginosa was considerably greater than in Escherichia coli. The uptake of the cis‐α‐[Ru(phen)(bb₁₂)]²⁺ complex into live P. aeruginosa was confirmed by using fluorescence microscopy. The water/octanol partition coefficients (log P) were determined to gain understanding of the relative cellular uptake. The cis‐α‐ and cis‐β‐[Ru(phen)(bb_n)]²⁺ complexes exhibited relatively strong binding to DNA (K_b≈10⁶ M ^?1), but no significant difference between the geometric isomers was observed.