Department of Chemistry, Villanova University, Villanova, Pennsylvania 19085, United States.
Department of Chemistry, Emory University, Atlanta, Georgia 30322, United States.
ACS Infect Dis. 2023 Apr 14;9(4):943-951. doi: 10.1021/acsinfecdis.2c00624. Epub 2023 Mar 16.
Quaternary ammonium compounds (QACs) serve as a first line of defense against infectious pathogens. As resistance to QACs emerges in the environment, the development of next-generation disinfectants is of utmost priority for human health. Balancing antibacterial potency with environmental considerations is required to effectively counter the development of bacterial resistance. To address this challenge, a series of 14 novel biscationic quaternary phosphonium compounds (bisQPCs) have been prepared as amphiphilic disinfectants through straightforward, high-yielding alkylation reactions. These compounds feature decomposable or "soft" amide moieties in their side chains, anticipated to promote decomposition under environmental conditions. Strong bioactivity against a panel of seven bacterial pathogens was observed, highlighted by single-digit micromolar activity for compounds P6P-12A,12A and P3P-12A,12A. Hydrolysis experiments in pure water and in buffers of varying pH revealed surprising decomposition of the soft QPCs under basic conditions at the phosphonium center, leading to inactive phosphine oxide products; QPC stability (>24 h) was maintained in neutral solutions. The results of this work unveil soft QPCs as a potent and environmentally conscious new class of bisQPC disinfectants.
季铵化合物（QACs）是抵御感染性病原体的第一道防线。随着环境中 QAC 耐药性的出现，开发下一代消毒剂对人类健康至关重要。为了有效对抗细菌耐药性的发展，需要在抗菌效力和环境考虑之间取得平衡。为了应对这一挑战，我们通过简单、高产的烷基化反应，制备了一系列 14 种新型双阳离子季膦盐化合物（bisQPC）作为两亲性消毒剂。这些化合物在侧链中具有可分解或“软”酰胺部分，预计在环境条件下会促进分解。我们观察到这些化合物对七种细菌病原体表现出很强的生物活性，其中化合物 P6P-12A,12A 和 P3P-12A,12A 的活性达到了个位数微摩尔。在纯水中和不同 pH 值的缓冲液中的水解实验表明，在碱性条件下，软 QPC 在磷中心发生了令人惊讶的分解，生成了无活性的氧化膦产物；在中性溶液中，QPC 稳定性（>24 h）得以保持。这项工作的结果揭示了软 QPC 是一种具有潜力且环保意识的新型双阳离子季膦盐消毒剂。
