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.

Benzalkonium chloride (BAC) and cetyl pyridinium chloride (CPC) are two of the most common household antiseptics, but show weaker efficacy against Gram-negative bacteria as well as against methicillin-resistant Staphylococcus aureus (MRSA) strains, relative to other S. aureus strains. We prepared 28 novel quaternary ammonium compounds (QACs) that represent a hybrid of these two structures, using 1- to 2-step synthetic sequences. The biscationic (bisQAC) species prepared show uniformly potent activity against six bacterial strains tested, with nine novel antiseptics displaying single-digit micromolar activity across the board. Effects of unequal chain lengths of two installed side chains had less impact than the overall number of side chain carbon atoms present, which was optimal at 22–25 carbons. This is further indication that simple refinements to multiQAC architectures can show improvement over current household antiseptics.