Self-Aggregation, Antimicrobial Activity and Cytotoxicity of Ester-Bonded Gemini Quaternary Ammonium Salts: The Role of the Spacer

Five ester-bonded gemini quaternary ammonium surfactants C(12)-E(n)-C(12) (n = 2, 4, 6), with a flexible spacer group, and C(12)-B(m)-C(12) (m = 1, 2), with rigid benzene spacers, were synthesized via a two-step reaction and analyzed. Furthermore, the effects of the spacer structure, spacer length and polymerization degree on the self-aggregation, antimicrobial activity and cytotoxicity of C(12)-E(n)-C(12) and C(12)-B(m)-C(12) and their corresponding monomer N-dodecyl-N,N,N-trimethyl ammonium chloride DTAC were investigated. The results showed that C(12)-E(n)-C(12) and C(12)-B(m)-C(12) had markedly lower critical micellar concentration (CMC) values and lower surface tension than DTAC. Moreover, the CMC values of C(12)-E(n)-C(12) and C(12)-B(m)-C(12) decreased with increasing spacer length. In the case of equivalent chain length, the rigidity and steric hindrance of phenylene and 1,4-benzenediyl resulted in larger CMC values for C(12)-B(m)-C(12) than for C(12)-E(n)-C(12). The antibacterial ability of C(12)-E(n)-C(12) and C(12)-B(m)-C(12) was assessed using Escherichia coli (E. coli) and Staphylococcus albus (S. aureus) based on minimum inhibitory concentrations (MICs). Furthermore, C(12)-E(n)-C(12) and C(12)-B(m)-C(12) exhibited higher antimicrobial activity than DTAC and had stronger function toward S. aureus than E. coli. The antimicrobial activity was enhanced by increasing the spacer chain length and decreased with the increased rigidity of the spacers. The cytotoxic effects of C(12)-E(n)-C(12) and C(12)-B(m)-C(12) in cultured Hela cells were evaluated by the standard CCK8 method based on half-maximal inhibitory concentration (IC(50)). The cytotoxicity of C(12)-E(n)-C(12) and C(12)-B(m)-C(12) was significantly lower than alkanediyl-α,ω-bis(dimethyldodecylammonium) bromide surfactants and DTAC. The spacer structure and the spacer length could induce significant cytotoxic effects on Hela cells. These findings indicate that the five ester-bonded GQASs have stronger antibacterial activity and lower toxicity profile, and thus can be used in the pharmaceutical industry.