title: Ester- and amide-containing multiQACs: Exploring multicationic soft antimicrobial agents.
abstract: 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 ∼1μM. 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.
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Allen
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Jennings
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Myles A
authors.initials: MA
authors.lastname: Mitchell
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States.
authors.forename: Saleh E
authors.initials: SE
authors.lastname: Al-Khalifa
authors.affiliation: Department of Chemistry, Temple University, Philadelphia, PA 19122, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Wuest
authors.affiliation: Department of Chemistry, Villanova University, Villanova, PA 19085, United States. Electronic address: kevin.minbiole@villanova.edu.
authors.forename: Kevin P C
authors.initials: KPC
authors.lastname: Minbiole
mesh_terms: D000577:Amides / Q000737:chemistry*; D000890:Anti-Infective Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004202:Disinfectants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004952:Esters / Q000737:chemistry*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000577:Amides; D000890:Anti-Infective Agents; D004202:Disinfectants; D004952:Esters; D000644:Quaternary Ammonium Compounds
keywords: Antiseptics; Methicillin-resistant Staphylococcus aureus (MRSA); Quaternary ammonium compounds; Soft antimicrobials