Rigidity-Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria

Abstract

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.

Keywords: Amphiphiles; Antimicrobial; Disinfectants; Phosphorus; QPCs.

Figure 1.

Previous efforts on rigidity-activity relationships in bisQACs.

Figure 2.

Anticipated preparation of a series of bisQPCs with varying linker rigidity.

Figure 3.

ORTEP diagrams for P2P-8,8 I (left) and P-2E-P-8,8 I₃ (right), as a result of alkyne reduction. Bond lengths for the bridging P-C and C-C bonds are labeled in Å. Thermal ellipsoids are shown at the 50% probability level. Except for the hydrogens on the alkene, all other hydrogen atoms are omitted for clarity.

Scheme 1.

Synthesis of P2P-n,n I series, P-2E-P-n,n I series; P-2E-P-n,1 series.

Scheme 2.

Attempted synthesis of P-2Y-P-n,n.