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

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) <i>tris</i>(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 <i>Acinetobacter baumannii</i> and <i>Klebsiella pneumoniae</i>. These <i>in vitro</i> studies revealed that the bioactivity of the overall <i>tris</i>(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 <i>A. baumannii</i> and 3.1-6.2 μM for MDR <i>K. pneumoniae</i>. 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).