Design, synthesis, and biological activity of novel ammonium salts containing sterically hindered phenolic fragment and phosphoryl group

Starodubtseva, R. R.; Гибадуллина, Э. М.; Pazilova, N. B.; Sapunova, Аnastasiia S.; Voloshina, Alexandra D.; Sudakov, Igor A.; Vyshtakalyuk, A. B.; Пудовик, М. А.; Бурилов, А. Р.; Бухаров, С. В.

doi:10.1039/c8md00481a

Cited by 13 publications

(2 citation statements)

References 42 publications

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“…Previous studies, including our own, have focused on elucidating structure–activity relationships (SARs) and structure–resistance relationships (SRRs) to enable the rational design of novel QAC compounds. These studies provided insights into the number and ratio of charges, length and types of side chains, core structural rigidity, and the inclusion of organometallic substituents have all contributed to the advancement of discovering next-generation QAC scaffolds. ,− …”

Section: Introductionmentioning

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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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…In our opinion, the combination of a phenolic substituent, a hydrazone moiety and an ammonium center in one molecule will solve the problem of the solubility of the target compounds in water along with high antioxidant and antimicrobial activities. The development of this study is based on our ongoing work on the design, synthesis and evaluation of the biological activity of positively charged isatin‐3‐acylhydrazones, and spatially hindered phenols . Our previous results showed that compounds containing a bulky phenolic fragment showed the best activity against Staphylococcus aureus ( Figure ) …”

Section: Introductionmentioning

confidence: 99%

Ammonium‐Charged Sterically Hindered Phenols with Antioxidant and Selective Anti‐Gram‐Positive Bacterial Activity

Богданов

Iskhakova

Voloshina

et al. 2020

Chemistry & Biodiversity

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The increase in the resistance of pathogens, in particular Staphylococcus aureus, to the action of antibiotics necessitates the search for new readily available and non-toxic drugs. In solving this problem, phenolic acylhydrazones have high potential. In this communication, the synthesis of quaternary ammonium compounds containing a differently substituted phenolic moiety has been performed. An initial study of antimicrobial activity showed that these compounds are highly selective against S. aureus and B. cereus. The highest activity (MIC 2.0 μM) was shown by hydrazones containing a catechol fragment. These compounds are more than 3-fold more active against S. aureus and 3 -10-fold more active against B. cereus than norfloxacin. Low hemolytic and high antioxidant activities of all new compounds were also established.

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Further Investigations into Rigidity‐Activity Relationships in BisQAC Amphiphilic Antiseptics

et al. 2020

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Thirty‐six biscationic quaternary ammonium compounds were efficiently synthesized in one step to examine the effect of molecular geometry of two‐carbon linkers on antimicrobial activity. The synthesized compounds showed strong antimicrobial activity against a panel of both Gram‐positive and Gram‐negative bacteria, including methicillin‐resistant Staphylococcus aureus (MRSA). While the linker geometry showed only a modest correlation with antimicrobial activity, several of the synthesized bisQACs are promising potential antiseptics due to good antimicrobial activity (MIC≤2 μM) and their higher therapeutic indices compared to previously reported QACs.

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Design, synthesis, and biological activity of novel ammonium salts containing sterically hindered phenolic fragment and phosphoryl group

Abstract: Novel multifunctional ammonium salts was obtained with high antimicrobial, antioxidant and low cytotoxic activity.

Cited by 13 publications

References 42 publications

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

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

Ammonium‐Charged Sterically Hindered Phenols with Antioxidant and Selective Anti‐Gram‐Positive Bacterial Activity

Further Investigations into Rigidity‐Activity Relationships in BisQAC Amphiphilic Antiseptics

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