Extending the architecture of bolaamphiphilic disinfectants: an investigation of octenidine and isooctenidine analogs

Quaternary ammonium compounds (QACs) have been used in commercial disinfectants since the mid-1900s due to their strong antimicrobial activity and relatively low toxicity to eukaryotic cells. However, antimicrobial resistance to common disinfectant compounds has compromised their effectiveness over the past decades. The growing threat of resistant microbial pathogens has resulted in a need for novel QACs bearing new architectures and/or mechanisms of action. In light of this, our group has synthesized and investigated ∼1000 cationic biocides over the past 15 years. We have most recently turned our focus to octenidine, a potent biscationic QAC that is often used in the medical field as an effective antiseptic and to disinfect medical instruments. Octenidine is a bolaamphiphile, bearing two cationic residues separated by an alkyl linker; this architecture seems to provide strong activity against resistant bacteria. Its structural analog, isooctenidine, has been suggested to also possess potent antimicrobial activity, but with increased water solubility. To pursue this promising observation within an exciting disinfectant architecture, 24 isooctenidine analogs were synthesized, varying the carbon linker length and the length of the terminal alkyl chains. These compounds, along with octenidine and three of its structural analogs, were tested for bacterial inhibition; additionally, multiple pairs of octenidine and isooctenidine isomers were tested for water solubility and surface tension reduction. Ten different bolaamphiphilic QAC structures were found to inhibit an 8-strain panel of bacteria at single digit micromolar levels, but no differentiation was observed between isomeric compounds in either bioactivity or solution behavior.