Novel resorcin[4]arene-based octacationic quaternary ammonium compounds (ResQACR) 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 ResQACR derivatives were studied by in vitro biological investigations. We identified that the ResQACbutyl derivative shows an impressive bacteriostatic activity against S. aureus. A remarkable multivalent effect was observed for this bacteriostatic activity. Interestingly, cytotoxic studies indicate that ResQACbutyl 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. ResQACundecyl 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. ResQACphenyl 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 C2v conformation of ResQACphenyl, which hinders optimal matching between the cationic chains and the negatively charged bacterial surface.
