Synthesis of C(28)-linker derivatives of betulinic acid bearing phosphonate group

Tsepaeva, O. V.; Nemtarev, A. V.; Grigor’eva, Leysan R.; Миронов, В. Ф.

doi:10.1007/s11172-021-3074-x

Cited by 5 publications

(1 citation statement)

References 37 publications

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“…We envisioned that this may be achieved through quaternization of phenylphosphine compounds such as 1,3-bis(diphenylphosphino)propane (dppp) and triphenylphosphine (TPP) due to their ubiquity in organic synthesis , and relative air-stabilities . Furthermore, previous studies have demonstrated promising antimicrobial activity for TPP derivatives against Gram-positive bacteria, − although a systematic investigation into TPP-based QPC architectures remains unexplored. Additionally, while several of these previously synthesized TPP derivatives have shown low micromolar antimicrobial activities, efflux pump-mediated resistance to TPP-derived QPCs has precluded their widespread utility. − Therefore, we began our investigations with the synthesis of TPP- and dppp-derived QPCs bearing hydrocarbon tails of varying lengths (Figure B), seeking to interrogate whether increasing the amphiphilic and cationic nature of the QPCs may increase broad-spectrum antimicrobial activity and aid in the evasion of efflux-pump-mediated resistance.…”

Section: Resultsmentioning

confidence: 99%

Quaternary Phosphonium Compounds: An Examination of Non-Nitrogenous Cationic Amphiphiles That Evade Disinfectant Resistance

et al. 2022

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Quaternary ammonium compounds (QACs) serve as mainstays in the formulation of disinfectants and antiseptics. However, an over-reliance and misuse of our limited QAC arsenal has driven the development and spread of resistance to these compounds, as well as co-resistance to common antibiotics. Extensive use of these compounds throughout the COVID-19 pandemic thus raises concern for the accelerated proliferation of antimicrobial resistance and demands for next-generation antimicrobials with divergent architectures that may evade resistance. To this end, we endeavored to expand beyond canonical ammonium scaffolds and examine quaternary phosphonium compounds (QPCs). Accordingly, a synthetic and biological investigation into a library of novel QPCs unveiled biscationic QPCs to be effective antimicrobial scaffolds with improved broad-spectrum activities compared to commercial QACs. Notably, a subset of these compounds was found to be less effective against a known QAC-resistant strain of MRSA. Bioinformatic analysis revealed the unique presence of a family of small multiresistant transporter proteins, hypothesized to enable efflux-mediated resistance to QACs and QPCs. Further investigation of this resistance mechanism through efflux-pump inhibition and membrane depolarization assays illustrated the superior ability of P6P-10,10 to perturb the cell membrane and exert the observed broad-spectrum potency compared to its commercial counterparts. Collectively, this work highlights the promise of biscationic phosphonium compounds as next-generation disinfectant molecules with potent bioactivities, thereby laying the foundation for future studies into the synthesis and biological investigation of this nascent antimicrobial class.

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