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.

Development of Membrane-Active Honokiol/Magnolol Amphiphiles as Potent Antibacterial Agents against Methicillin-Resistant Staphylococcus aureus (MRSA)

“…Additionally, the effect of the n = 3 linker length of honokiol/magnolol derivatives on the antibacterial activities against S. aureus was similar to that of the n = 3 linker length of some quaternary ammonium compounds (QAC) reported by Minbiole and co-workers. 48,49 Additionally, to further validate that the precursors honokiol and magnolol are crucial for the antibacterial activity, we replaced the honokiol/magnolol moiety with phenol and 4allylphenol, preparing compounds 7 and 8 by the same method as 5i (Scheme S1) and evaluating their antibacterial activities against S. aureus and 10 clinical MRSA isolates. The MICs of 7 and 8 were all greater than 64 μg/mL (Table S2), indicating that the honokiol/magnolol part plays an important role in the antibacterial activity.…”

Quaternary Ammonium Compounds (QACs) and Ionic Liquids (ILs) as Biocides: From Simple Antiseptics to Tunable Antimicrobials

“…A significant contribution to the development of QACs as a class of cationic biocides was made by the groups of Wuest and Minbiole (Figure 17) [71][72][73][74][75][76]. It was found that close structural analogs of BAC 37 containing amide and ester groups exhibited comparable activity and lower toxicity than BAC [76].…”

“…A significant contribution to the development of QACs as a class of cationic biocides was made by the groups of Wuest and Minbiole (Figure 17) [71][72][73][74][75][76]. It was found that close structural analogs of BAC 37 containing amide and ester groups exhibited comparable activity and lower toxicity than BAC [76]. QAC derivatives of natural compounds (quinine 38 and nicotine 39) demonstrated a wide spectrum of antibacterial action, thus justifying the search for other platforms of natural origin to expand the library of active QAC compounds [74].…”

“…Wuest and Minbiole developed a simple synthetic route for obtaining tris-and tetra-QACs on the basis of polyamine platforms 93-97 (Figure 31) [71,72,76,140]. The activity of multi-QACs was significantly higher than that of mono-QACs but was comparable to that of bis-QACs.…”

Biomolecular interactions of lysosomotropic surfactants with cytochrome c and its effect on the protein conformation: A biophysical approach

“…Several soft cationic QACs showed biological activities against several pathogenic bacterial strains [16], filamentous fungi [17] and also some human tumor cell lines [18]. Therefore, soft cationic QACs can potentially be used in lysosometargeting anti-cancer drugs [19][20][21]. Cationic QACs can enter the lysosome and possibly induce conformational changes of the proteins involved in apoptosis [22].…”