Rigidity‐Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria

Biscationic quaternary phosphonium compounds (bisQPCs) represent a promising class of antimicrobials, displaying potent activity against both Gram‐negative and Gram‐positive bacteria. In this study, we explored the effects of structural rigidity on the antimicrobial activity of QPC structures bearing a two‐carbon linker between phosphonium groups, testing against a panel of six bacteria, including multiple strains harboring known disinfectant resistance mechanisms. Using simple alkylation reactions, 21 novel compounds were prepared, although alkene isomerization as well as an alkyne reduction were observed during the respective syntheses. The resulting bisQPC compounds showed strong biological activity, but were hampered by diminished solubility of their iodide salts. One compound (P2P‐10,10 I) showed single‐digit micromolar activity against the entire panel of bacteria. Overall, intriguing biological activity was observed, with less rigid structures displaying better efficacy against Gram‐negative strains and more rigid structures demonstrating slightly increased efficacy against S. aureus strains. Strength from the core: The COVID‐19 pandemic has increased the use of already‐ubiquitous quaternary ammonium compounds (QACs), but QAC‐resistance mechanisms are increasingly prevalent in bacteria. Our groups are developing improved disinfectants of distinctly different structures, and herein we expand our work in an entirely new class of molecules, the quaternary phosphonium compounds (QPCs), to explore rigidity‐activity relationships in biscationic structures (bisQPCs).