Homoleptic gallium(iii) and indium(iii) tris(flavonolate) complexes: influence of the metal ion on antibacterial activity and mammalian cell viability

Abstract

The requirement for novel chemical entities to combat multidrug-resistant bacteria has stimulated renewed interest in metal-derived antibacterial agents. In this regard, gallium(III)-based salts and chelate complexes have shown promising antibacterial and anti-virulence activities, while the therapeutic potential of indium(III)-derived compounds is relatively unexplored. Herein, we report the synthesis and characterisation of a series of homoleptic Ga(III) and In(III) tris(flavonolate) complexes with composition [ML₃] (where M = Ga(III), In(III), L = flavonolate), prepared from the reaction of eight substituted flavonols (3-hydroxyflavones) with the corresponding metal nitrate. The Ga(III) and In(III) complexes derived from 3′,4′-dimethoxy-3-hydroxyflavone and 3′,4′,5′-trimethoxy-3-hydroxyflavone were investigated for toxicity towards mouse fibroblasts, and antibacterial activity towards multidrug-resistant (MDR) strains of clinically relevant pathogens Acinetobacter baumannii and Klebsiella pneumoniae. These in vitro studies revealed that the bioactivity of the overall tris(flavonolate) complex is highly dependent on the nature of the metal ion and substitution pattern of the flavonolate ligands. The Ga(III) complexes did not affect the viability of fibroblasts (IC₅₀ > 100 μM) yet displayed good antibacterial activity towards all bacterial strains: MIC 12.5 μM towards MDR A. baumannii and 3.1–6.2 μM for MDR K. pneumoniae. In strong contrast, the analogous In(III) complexes exhibited toxicity towards fibroblasts (IC₅₀ 14.4 and 52.4 μM) while remaining relatively inactive towards the bacterial pathogens (MIC 100 μM).