Quaternary ammonium compounds (QACs) are a key class of antiseptics. Recent investigations into their construction have uncovered novel and potent multicationic variants. Based on a triscationic "trisQAC" precedent, we have implemented a scaffold-hopping approach to develop alternative QAC architectures that display 1-3 long alkyl chains in specific projections from cyclic and branched core structures that bear 3-4 nitrogen atoms. The preparation of 30 QAC structures has allowed for correlation of scaffold structure with antimicrobial activity. We identified select QACs with limited conformational flexibility that have improved bioactivity against planktonic bacteria as compared to their linear counterparts. We also confirmed that resistance, as evidenced by an increased minimum inhibitory concentration (MIC) for methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) compared to methicillin-susceptible <i>Staphylococcus aureus</i> (MSSA), can reduce efficacy up to 64-fold for monocationic QACs. Differentiation of antimicrobial and anti-biofilm activity, however, was not observed, implying that these compounds utilize a non-specific mode of eradication.

Scaffold-hopping of multicationic amphiphiles yields new classes of antimicrobials

251st National Meeting (2016)

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