ABSTRACT
Quaternary ammonium compounds have served as a first line of protection for human health as surface disinfectants and sanitizers for nearly a century. However, increasing levels of bacterial resistance have spurred the development of novel QAC architectures. In light of the observed reduction in eukaryotic cell toxicity when the alkyl chains on QACs are shorter in nature (≤10C), we prepared 47 QAC architectures that bear multiple short alkyl chains appended to up to three cationic groups, thus rendering them "bushy-tailed" multiQACs. Antibacterial activity was strong (often ~1-4 µM) in a varied set of bushy-tailed architectures, though observed therapeutic indices were not significantly improved over QAC structures bearing fewer and longer alkyl chains.
ABSTRACT
Cationic biocides play a crucial role in the disinfection of domestic and healthcare surfaces. Due to the rise of bacterial resistance towards common cationic disinfectants like quaternary ammonium compounds (QACs), the development of novel actives is necessary for effective infection prevention and control. Toward this end, a series of 15 chimeric biscationic amphiphilic compounds, bearing both ammonium and phosphonium residues, were prepared to probe the structure and efficacy of mixed cationic ammonium-phosphonium structures. Compounds were obtained in two steps and good yields, with straightforward and chromatography-free purifications. Antibacterial activity evaluation of these compounds against a panel of seven bacterial strains, including two MRSA strains as well as opportunistic pathogen A. baumannii, were encouraging, as low micromolar inhibitory activity was observed for multiple structures. Alkyl chain length on the ammonium group was, as expected, a major determinant of bioactivity. In addition, high therapeutic indexes (up to 125-fold) for triphenyl phosphonium-bearing amphiphiles were observed when comparing antimicrobial activity to mammalian cell lysis activity.
