Bushy‐Tailed Multicationic Quaternary Phosphonium Compounds: Potent Amphiphilic Disinfectants with Promising Therapeutic Indices
Year: 2024
Type: article
Abstract: Quaternary ammonium compounds (QACs) have been essential for protecting human health for almost a century, functioning as surface disinfectants and sanitizers. With bacterial resistance increasing against commercially available QACs, the development of novel antimicrobials with divergent architectures is essential for effective infection prevention and control. Toward this end, our group has expanded beyond traditional ammonium scaffolds and explored the development of quaternary phosphonium compounds (QPCs). Herein, we report the synthesis and biological investigation of a series of 20 novel multicationic QPCs, bearing multiple short alkyl or aryl chains, also referred to as "bushy-tailed" multiQPCs; these structures were hypothesized to have strong bioactivity while displaying low mammalian toxicity. Select bushy-tailed QPC derivatives with trishexylphosphonium groups displayed single-digit or sub-micromolar activity against all seven bacteria tested, and MIC values of 2- to 8-fold better than their bushy-tailed QAC counterparts. Importantly, therapeutic indices of these bushy-tailed QPCs were favorable in many cases, and were ≥4 against the entire bacterial panel for pX-P6*,P6* and 1,8-P6*,P6*, superior to more traditional architectures. This work highlights the promise of a novel set of multicationic phosphonium compounds as novel disinfectants with potent bioactivities and low toxicity.
Source: ChemMedChem
Institutions: Villanova University, Emory University
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: bronze
Awards: G1185567861, MRI: Acquisition of a Liquid Chromatography Tandem Mass Spectrometer to Enhance Undergraduate Research and Teaching at a Primarily Undergraduate Institution, G1627413954, G1927708617, G4303786622, MRI: Acquisition of a 500 MHz Nuclear Magnetic Resonance (NMR) Spectrometer to Enhance Undergraduate Research and Teaching at a Primarily Undergraduate Institution, G5392122003, G7943627007, Natural Product-Inspired Approaches Toward The Development Of Antivirulence And Species-Specific Inhibitors
OpenAlex ID: W4403713646