Aryl bismuth phosphinates [BiAr2(O(O)PRR′)]: structure–activity relationships for antibacterial activity and cytotoxicity

Abstract

To study and evaluate the structure–activity relationships in di-aryl bismuth phosphinates on antibacterial activity and cytotoxicity a series of complexes containing ortho-methoxyphenyl, meta-methoxyphenyl, meta-tolyl and para-tolyl aryl groups; [Bi(o-MeOPh)₂(O(O)P(H)Ph)]_n1, [Bi(o-MeOPh)₂(O(O)PPh₂)]_n2, [Bi(o-MeOPh)₂(O(O)P(p-MeOPh)₂)]_n3, [Bi(m-MeOPh)₂(O(O)P(H)Ph)]_n4, [Bi(m-MeOPh)₂(O(O)PPh₂)]_n5, [Bi(m-MeOPh)₂(O(O)P(p-MeOPh)₂)]_n6, [Bi(m-tol)₂(O(O)P(H)Ph)]_n7, [Bi(m-tol)₂(O(O)PPh₂)]_n8, [Bi(m-tol)₂(O(O)P(p-MeOPh)₂)]_n9, [Bi(p-tol)₂(O(O)P(H)Ph)]_n10, [Bi(p-tol)₂(O(O)PPh₂)]_n11 and [Bi(p-tol)₂(O(O)P(p-MeOPh)₂)]_n12, were synthesised and characterised. Complexes 4, 7, 8, 10 and 11 were structurally authenticated by X-ray crystallography. Evaluation of their antibacterial activity towards methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), Escherichia coli (E. coli) and Pseudomonas aeruginosa (P. aeruginosa) showed that the bismuth bound aryl group has a profound influence on activity, with the o-MeOPh complexes 1–3 showing very little activity while the m-MeOPh complexes have the greatest activity towards MRSA and VRE in the range of 0.63 to 1.25 μM. Viability studies with Cos-7 cells showed that the di-aryl bismuth complexes 1–12 are less cytotoxic than their di-phenyl bismuth analogues, with a general trend of toxicity observed as p-tolyl > m-tolyl > m-methoxyphenyl > o-methoxyphenyl. The large difference in Cos-7 viability for complexes 1 (IC₅₀ > 80 μM) and 4 (IC₅₀ 14.0 μM) was further investigated through bismuth uptake studies, where there was no obvious difference in Cos-7 bismuth uptake at 5 μM. This suggests that the bismuth-bound aryl group has a significant impact on biological activity, which is then further mediated by other ligands.