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, bioactivity against a panel of 6 bacteria including MRSA strains was strong for bisQAC structures, and clearly correlated to the length of non-polar side chains. Modest advantages were noted for amide-containing side chains, as compared to 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 submicromolar activity against a MRSA strain.

Further Investigations into Rigidity‐Activity Relationships in BisQAC Amphiphilic Antiseptics

“…Recently, our group reported a modest, but significant trend relating increased core rigidity of diamine‐based bisQACs with increased antimicrobial activity . These results suggested that the relative disposition of the nonpolar, alkyl chains may affect antimicrobial activity, with rigid 180° separation of the alkyl chains leading to higher antimicrobial activity.…”

“…Overall, this work sought to further probe the rigidity‐activity relationships previously observed by our research group . We successfully synthesized 36 novel bisQACs with varied two‐carbon linker geometry based on alkane, alkene and alkyne cores, with the goal of assessing the effect of QAC geometry on antimicrobial activity.…”

“…Recently, our group reported a modest, but significant trend relating increased core rigidity of diamine-based bisQACs with increased antimicrobial activity. [7] These results suggested that the relative disposition of the nonpolar, alkyl chains may affect antimicrobial activity, with rigid 180°separation of the alkyl chains leading to higher antimicrobial activity. Based on the previous success by our group and others with pyridiniumbased bis-and multiQACs with strong antimicrobial activity (MIC � 1 μM), [8] including a pyridinium-based bisQAC with a simple three carbon linker, we surmised that well-defined QAC geometries could be obtained in pyridinium-based bisQACs with different linker geometries.…”

Synthesis and Antibacterial Evaluation of Bis‐thiazolium, Bis‐imidazolium, and Bis‐triazolium Derivatives

“…Mono-ammonium compounds such as benzalkonium chloride or cetylpyridinium chloride were followed by bis-ammonium compounds such as dequalinium chloride and chlorhexidine. [9,10] In addition, other recente fforts led to the designo fp owerful molecules that show very low toxicity toward mammalian cells. They also suggest that some derivatives of this class could be used foro ther purposes than simple topical administration.…”

“…Thus, some efforts have been made to correlate the structural features of QACs and both their antibacterial activity and eukaryotic toxicity. [9,10] In addition, other recente fforts led to the designo fp owerful molecules that show very low toxicity toward mammalian cells. [11] Besides, QACs maye xhibit antimalarial activity,a nd someb is-cationicd erivatives provedt ob e very potent both in vitro and in vivo.…”