Synthesis and Exploration of the Antimicrobial Potential of Glycoluril-derived Quaternary Ammonium Compounds

The growing antimicrobial resistance necessitates the search for novel broad-spectrum antimicrobial agents, with multicationic quaternary ammonium compounds (multi-QACs) potentially serving as promising candidates. This research work focuses on the synthesis of a new generation of tetracationic QACs (tetra-QACs) based on glycoluril as a linker, as well as the investigation of the antimicrobial potential of the obtained compounds. A series of 6 compounds with varying lengths of aliphatic substituents was synthesized. The products were characterized by high-resolution mass spectrometry (HRMS), one-dimensional 1H and 13C NMR spectroscopy, including 13C DEPT-135, and two-dimensional 1H COSY and 1H-13C HSQC experiments. Antimicrobial activity was evaluated against five multidrug-resistant bacteria from the ESKAPE group and the yeast-like fungus Candida auris. The novel tetra-QACs demonstrated high efficacy against the selected pathogen panel, surpassing the properties of the reference antiseptic cetylpyridinium chloride against planktonic cells with minimum inhibitory concentration (MIC) and minimum bactericidal concentration equal to 0.5 mg/L and 1 mg/L, respectively, against Staphylococcus aureus. The activity of the investigated tetra-QACs was 8 times higher than that of the second standard, octenidine dihydrochloride, against biofilms of the gram-negative bacterium Acinetobacter baumannii. The compounds also exhibited strong fungicidal activity with MIC of 0.5 mg/L and minimum fungicidal concentration of 8 mg/L against Candida auris. The structure-activity relationship within the series was also studied. Compounds with hydrophobic substituents ranging from 7 to 8 carbon atoms demonstrated the best bactericidal properties, while the most pronounced antifungal efficacy was observed for substances with C8 and C10 alkyl tails.