LAUSR

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 like Acinetobacter baumannii and Pseudomonas 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.