Redox-Active Quinazolinone Thioamide Ag(I) Complexes with Potent Antibacterial Activity: Mechanistic Insights and Hydrogel-Enhanced Efficacy

The antibacterial properties of Ag(I) coordination compounds are well documented; however, their effectiveness is highly dependent on the choice of appropriate ligands, and it is frequently hindered by their low water solubility and limited bioavailability. Herein, six new Ag(I) complexes incorporating the quinazolinone thioamide mqztH (=2-mercapto-4(3H)-quinazolinone) and phosphine co-ligands were synthesized and investigated for their antibacterial activity. In vitro activity assays against <i>Escherichia coli</i> (<i>E. coli</i>) and <i>Staphylococcus aureus</i> (<i>S. aureus)</i> bacterial strains revealed that all complexes selectively inhibited <i>S. aureus</i> bacterial growth. Structure-activity relationship analysis showed that monodentate PPh₃ co-ligands play a key role in enhancing the antibacterial efficacy of their complexes. Notably, complex [AgCl(mqztH)(PPh₃)₂] (<b>1</b>) exhibited broad-spectrum activity, with IC₅₀ values of 4.2 ± 1.4 μg mL^-1 (4.9 μΜ) for <i>S. aureus</i> and 63 ± 1.9 μg mL^-1 (75 μΜ) for <i>E. coli</i> bacteria. To improve solubility and antibacterial activity, complex <b>1</b> was encapsulated in barium alginate (<b>BaAlg</b>) matrices to form hydrogel-based drug delivery formulations <b>[1]@BaAlg</b>. The synthesized formulations retained the bactericidal effect of the complex, achieving comparable activity at concentrations lower by an order of magnitude compared to complex <b>1</b> in free form. Combined with the demonstrated high biocompatibility of complex <b>1</b> toward L929 normal eukaryotic cells, as well as the biocompatible nature of the alginate matrix, these findings underscore the strong potential of the complex <b>1</b>-loaded hydrogel formulations for further investigation and development as effective antibacterial drug platforms. Mechanistic studies confirmed the redox-active nature of complex <b>1</b> and its potential to inhibit the function of glutathione reductase (GR) and thioredoxin reductase (TrxR) at low concentrations, suggesting the interference with bacterial redox homeostasis as a relevant mechanism of bioactivity.