Novel octacationic-resorcin[4]arenes featuring quaternary ammonium groups as multivalent biocides

Abstract

Novel resorcin[4]arene-based octacationic quaternary ammonium compounds (ResQAC^R) were obtained by linking tetraalkylammonium groups on the macrocycle wider rim to give multivalent multi-QACs. Their structures were elucidated through 1D and 2D NMR experiments, HR-MS analysis, and crystallographic studies. Additionally, the conformational dynamics of these octacationic-resorcinarenes were investigated using ¹H variable-temperature (VT) NMR experiments. The antimicrobial properties of ResQAC^R derivatives were studied by in vitro biological investigations. We identified that the ResQAC^butyl derivative shows an impressive bacteriostatic activity against S. aureus. A remarkable multivalent effect was observed for this bacteriostatic activity. Interestingly, cytotoxic studies indicate that ResQAC^butyl showed no adverse impact on cell viability of a human cell line, even at concentrations 30 times greater than the MIC for S. aureus and approximately 3 times higher than the MIC for E. coli. ResQAC^undecyl exhibits greater bacteriostatic activity against E. coli than against S. aureus, but it is cytotoxic at lower concentrations (IC₅₀ of 12.1 μM) than its MIC. ResQAC^phenyl shows scarce bacteriostatic activity against both S. aureus and E. coli, while no multivalent effect was observed. This is likely attributed to the conformational rigidity of the boat C_2v conformation of ResQAC^phenyl, which hinders optimal matching between the cationic chains and the negatively charged bacterial surface.