The versatile synthesis and biological evaluation of all-alkyl biscationic quaternary phosphonium compounds: atom-economical and potent disinfectants

Given the growing resistance to traditional quaternary ammonium compounds (QACs) - long used as primary disinfectants - there is an urgent need for structurally distinct alternatives to effectively combat infectious threats. Quaternary phosphonium compounds (QPCs) have recently emerged as a promising alternative class, demonstrating strong activity even against highly drug-resistant strains. Herein, we present a novel series of 16 all-alkyl biscationic QPCs, designed to expand the scope of atom-economical cationic biocides and evaluate their potential as next-generation disinfectants. Strong and broad bioactivity against a panel of eight bacterial pathogens was observed, with six analogs achieving single-digit micromolar activity across all strains tested. Structure-activity analysis revealed that optimal bioactivity correlates with 10-12 carbon alkyl side chains and longer charge-separating linkers (<i>m</i> = 8-10), which render the structures bolaamphiphilic. Comparisons between bisQAC and bisQPC analogs suggest that substituting the ammonium center with phosphonium had minimal impact on antimicrobial potency, but synthetic versatility allowed access to novel and potent QPC structures. This work underscores the potential of bisQPCs in the development novel and potent disinfectants.