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Allen RA , Jennings MC , Mitchell MA , Al-Khalifa SE , Wuest WM , Minbiole KPC
Ester- and amide-containing multiQACs: Exploring multicationic soft antimicrobial agents
Bioorg Med Chem Lett. 2017 May 15;27(10) :2107-2112
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Quaternary ammonium compounds (QACs) are ubiquitous antiseptics whose chemical stability is both an aid to prolonged antibacterial activity and a liability to the environment. Soft antimicrobials, such as QACs designed to decompose in relatively short times, show the promise to kill bacteria effectively but not leave a lasting footprint. We have designed and prepared 40 soft QAC compounds based on both ester and amide linkages, in a systematic study of mono-, bis-, and tris-cationic QAC species. Antimicrobial activity, red blood cell lysis, and chemical stability were assessed. Antiseptic activity was strong against a panel of six bacteria including two MRSA strains, with low micromolar activity seen in many compounds; amide analogs showed superior activity over ester analogs, with one bisQAC displaying average MIC activity of approximately 1muM. For a small subset of highly bioactive compounds, hydrolysis rates in pure water as well as buffers of pH =4, 7, and 10 were tracked by LCMS, and indicated good stability for amides while rapid hydrolysis was observed for all compounds in acidic conditions.
1464-3405 Allen, Ryan A Jennings, Megan C Mitchell, Myles A Al-Khalifa, Saleh E Wuest, William M Minbiole, Kevin P C Journal Article England Bioorg Med Chem Lett. 2017 May 15;27(10):2107-2112. doi: 10.1016/j.bmcl.2017.03.077. Epub 2017 Mar 29.