Atom Economical QPCs: Phenyl-Free Biscationic Quaternary Phosphonium Compounds as Potent Disinfectants

Abstract

Quaternary ammonium compounds (QACs) are vital disinfectants for the neutralization of pathogenic bacteria in clinical, domestic, and commercial settings. After decades of dependence on QACs, the emergence of antimicrobial resistance to this class of compounds threatens the ability of existing QAC products to effectively manage rising bacterial threats. The need for new disinfectants is therefore urgent, with quaternary phosphonium compounds (QPCs) emerging as a new class of promising antimicrobials that boast significant activity against highly resistant bacteria. Reported here is a series of twenty-one novel QPCs that replace phenyl substituents on the phosphorus center with alkyl groups yet allow for rapid synthetic routes in high yields. Within this series are structures containing methyl, ethyl, or cyclohexyl phosphonium substituents on bisphosphane scaffolds bearing ethyl linkers, affording atom economical structures and ones that represent exact analogs to nitrogenous amphiphiles. The resultant bisQPC structures display high antibacterial efficacy enjoyed by comparably constructed QACs, with three structures in the singledigit micromolar activity range despite structural simplification.

Chimeric Amphiphilic Disinfectants: Quaternary Ammonium/Quaternary Phosphonium Hybrid Structures

“…This is consistent with previous NMR chemical shift observations. [21] The bioactivities of the prepared cationic amphiphilic compounds were assessed via minimum inhibitory concentration (MIC) and red blood cell (RBC) hemolysis (lysis 20 ) assays, wherein the latter was used as a proxy for cytotoxicity. A representative commercial preparation of BAC (70 % benzyldimethyldodecylammonium chloride and 30 % benzyldimethyltetradecylammonium chloride) was tested as a control; the previously reported pX-12,12 served as a bisQAC reference for these chimeric compounds.…”

“…This might reflect the small calculated spread of cationic charge throughout the aromatic systems, which may in turn lead to increased resistance-to-resistance, although a phenyl advantage is not consistent with our previous reports of highly potent alkyl-based QPCs. [21] Red blood lysis values also provide insight into the selective bioactivity of these antimicrobial amphiphiles. Lysis 20 values were observed to be a modest 250 μM for all compounds with chains of 12 carbons or shorter.…”

“…[25] Chimeric compounds could take advantage of the bioactivity of both the QPC and QAC families, by presenting bacteria with two distinct "warhead" groups to stymie resistance mechanisms. Even subtle bioactivity differences between these two cationic groups, which we suspect to arise from previously-unmeasured charge density differences, [21] could exploit weaknesses in bacterial defenses. Accordingly, we set out to develop a series of chimeric molecules, amphiphiles that include both quaternary ammonium and quaternary phosphonium residues, in order to examine their antimicrobial capacities in comparison to amphiphiles of a single cationic element.…”

“…[15] While QPCs have found industrial applications and utility in enhancing the activity and transport of select bioactive agents, [16][17] the development of QPCs as standalone disinfectants or sanitizing agents is still in its infancy. Fortunately, multicationic QPCs are being actively explored by our group [18][19][20][21] and others. [22][23] Recently, these QPCs have been shown to have privileged properties against otherwise pan-drug resistant strains of Acinetobacter baumannii, [24] outperforming a variety of established disinfectants and potent antibiotics.…”

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

“…In particular, Toles et al remark the improvement in the efficiency of MHCS against some of the most worrisome bacteria that are currently circulating in the public space, such as Acinetobacter baumannii and Pseudomonas aeruginosa, which are exhibiting an increasing level of resistance to standard disinfectants. It is a generally held belief that Gram-negative bacteria, with the barrier function of the outer membrane, are more difficult to eradicate than Gram-positive bacteria [144,156,157]. Furthermore, it is estimated that approximately half of all illnesses are caused by Gram-negative Escherichia coli [158].…”