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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 pathogenA. 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. 

Abstract Over the past decades, the shortcomings of established quaternary ammonium disinfectants have become increasingly clear. Although benzalkonium chloride (BAC) has enjoyed nearly a century of significantly protecting human health through surgical preparation, home use, and industrial applications, increasing levels of bacterial resistance have rendered it decreasingly effective. In light of more recent efforts that have informed us that multicationic amphiphilic disinfectants show both higher activity as well as diminished susceptibility to resistance, we embarked on the preparation of 27 multicationic QACs in an attempt to clearly document structure‐activity relationships of next‐generation BAC structures. Select biscationic BAC derivatives demonstrate single‐digit micromolar activity against all seven bacteria tested and MIC values of 2‐ to 32‐fold better than BAC. Particularly notable is the improvement against the more concerning bacteria likeAcinetobacter baumanniiandPseudomonas aeruginosa, which pose a modern threat to legacy disinfectants like BAC. With simple synthetic paths, consistently high yields (averaging ∼80 %), and strong biological activity, potent structures with clear SAR trends and strong therapeutic indices have been established.