Scaffold‐Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials. Issue 16 (11th September 2015)

• Record Type: Journal Article
• Authors: Mitchell, Myles A.; Iannetta, Anthony A.; Jennings, Megan C.; Fletcher, Madison H.; Wuest, William M.; Minbiole, Kevin P. C.
• Is Part Of: Chembiochem. Volume 16:Issue 16(2015)
• Page Start: 2299
• Page End: 2303
• Publication Date: 2015-09-11
• Subjects: Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1002/cbic.201500381
• Languages: English
• ISSNs: 1439-4227

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>Quaternary ammonium compounds (QACs) are a vital class of antiseptics. Recent investigations into their construction are uncovering novel and potent multicationic variants. Based on a 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 bearing 3–4 nitrogen atoms. The preparation of 30 QAC structures allowed for correlation of scaffold structure with antimicrobial activity. We identified 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 <italic>Staphylococcus aureus</italic> (MRSA) compared to methicillin‐susceptible <italic>Staphylococcus aureus</italic> (MSSA), can reduce efficacy up to 64‐fold for monocationic QACs. Differentiation of antimicrobial and anti‐biofilm activity, however, was not observed, suggesting that these compounds utilize a non‐specific mode of eradication.</p> </abstract>