An Investigation into Rigidity-Activity Relationships in BisQAC Amphiphilic Antiseptics

Abstract

Twenty-one mono- and biscationic quaternary ammonium amphiphiles (monoQACs and bisQACs) were rapidly prepared in order to investigate the effects of rigidity of a diamine core structure on antiseptic activity. As anticipated, the bioactivity against a panel of six bacteria including methicillin-resistant Staphylococcus aureus (MRSA) strains was strong for bisQAC structures, and is clearly correlated with the length of non-polar side chains. Modest advantages were noted for amide-containing side chains, as compared with straight-chained alkyl substituents. Surprisingly, antiseptics with more rigidly disposed side chains, such as those in DABCO-12,12, showed the highest level of antimicrobial activity, with single-digit MIC values or better against the entire bacterial panel, including sub-micromolar activity against an MRSA strain.

Keywords: antiseptics; benzalkonium chloride; bisQAC; methicillin-resistant Staphylococcus aureus (MRSA); quaternary ammonium compounds.

Figure 1.

Displacement ellipsoid (50%) representation of pip-11,11 (top), pip-12,12 (middle), and pip-13,13 (bottom). Bromide ions have been omitted for clarity.

Scheme 1.

Conceptual overview of bisQACs of varied rigidity.

Scheme 2.

Synthesis of dialkyl piperazine QACs: a) 2.2 eq C_nH_2n+1Br, DMF, 120 °C, 6 h; b) 1.3 eq C_nH_2n+1Cl, CH₃CN, 80 °C, 20 h, 16%; c) 1.3 eq C_nH_2n+1Br, CH₃CN, 80 °C, 48 h, 8%.

Scheme 3.

Synthesis of piperazine QACs using amide-containing electrophiles: a) 2.2 eq bromoamide, CH₃CN, 80 °C, 3 h.

Scheme 4:

Preparation of DABCO-based QACs using alkyl- and amide-containing electrophiles: a) 2.2 eq C₁₂C₂₅Cl, CH₃CN, 80 °C, 24 h; b) 8 eq C₁₂C₂₅Br, CH₃CN, 80 °C, 48 h; c) 2.2 eq bromoamide, CH₃CN, 80 °C, 24 h.