Double BAC and Triple BAC: A Systematic Analysis of the Disinfectant Properties of Multicationic Derivatives of Benzalkonium Chloride (BAC)

Abstract

Over the past decades, the shortcomings of established quaternary ammonium disinfectants have become increasingly clear. Although benzalkonium chloride (BAC) has enjoyed nearly a century of significantly protecting human health through surgical preparation, home use, and industrial applications, increasing levels of bacterial resistance have rendered it decreasingly effective. In light of more recent efforts that have informed us that multicationic amphiphilic disinfectants show both higher activity as well as diminished susceptibility to resistance, we embarked on the preparation of 27 multicationic QACs in an attempt to clearly document structure‐activity relationships of next‐generation BAC structures. Select biscationic BAC derivatives demonstrate single‐digit micromolar activity against all seven bacteria tested and MIC values of 2‐ to 32‐fold better than BAC. Particularly notable is the improvement against the more concerning bacteria like Acinetobacter baumannii and Pseudomonas aeruginosa, which pose a modern threat to legacy disinfectants like BAC. With simple synthetic paths, consistently high yields (averaging ∼80 %), and strong biological activity, potent structures with clear SAR trends and strong therapeutic indices have been established.

Multiheaded Cationic Surfactants with Dedicated Functionalities: Design, Synthetic Strategies, Self-Assembly and Performance

“…Recent research investigations have demonstrated that in contrast to quaternary ammonium salts such as benzalkonium chloride (BAC), which have been used for decades, multicationic disinfectants are more effective and rarely lead to the development of resistance by various types of microorganisms [150,151]. The weaknesses of traditional quaternary ammonium disinfectants have become more apparent in the last few decades, so many research teams are working on the development of novel and more effective MHCS structures.…”

“…The multi-cationic homologs of benzalkonium chloride (BAC) are one of the structures that research teams are now working on, and they look the most promising. In the paper published by Toles et al [150], the researchers successfully obtained triscation BAC analogues (Tris-BAC) and showed that their antimicrobial activity was significantly greater than that of monocationic BAC. In this study, the authors demonstrated that multicationic derivatives of BAC had biological activity against the Gram-positive and Gram-negative bacteria in the single-digit micromolar range.…”

Polyamide film containing a molecularly imprinted polymer prepared on a paper surface by interfacial polymerization and its selective adsorption of benzalkonium chloride

“…BKC is water-soluble and widely used as an antibacterial agent, antiseptic, and preservative. [12][13][14] BKC has agricultural, industrial, and clinical applications. However, concerns about the safety of BKC, especially its mutagenicity and the bacterial resistance to BKC, have been reported.…”

“…In the present study, benzalkonium chloride (BKC) was the target pharmaceutical to be removed. BKC is water‐soluble and widely used as an antibacterial agent, antiseptic, and preservative 12–14 . BKC has agricultural, industrial, and clinical applications.…”

The Antimicrobial and Antibiofilm Potential of New Water-Soluble Tris-Quaternary Ammonium Compounds

“…The tris-QACs (especially with a pyridine core and three alkyl tails) as biocides have been studied very little. Currently, there are only a few works covering this subject [ 20 , 21 , 22 , 23 , 24 ] ( Figure 2 ).…”