Ester- and amide-containing multiQACs: Exploring multicationic soft antimicrobial agents

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Allen, Ryan A.¹  Jennings, Megan C.²  Mitchell, Myles A.¹  Al-Khalifa, Saleh E.¹  Wuest, William M.²  Minbiole, Kevin P. C.¹ 

[1] Villanova Univ, Dept Chem, Villanova, PA 19085 USA

[2] Temple Univ, Dept Chem, Philadelphia, PA 19122 USA

关键词: Antiseptics;    Methicillin-resistant Staphylococcus aureus (MRSA);    Quaternary ammonium compounds;    Soft antimicrobials;   

DOI  :  10.1016/j.bmcl.2017.03.077

来源: Elsevier

【 摘 要 】

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 similar to 1 mu M. 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free