Design and synthesis of amphiphilic 2-hydroxybenzylphosphonium salts with antimicrobial and antitumor dual action

Terekhova, Natalia V.; Татаринов, Д. А.; Shaihutdinova, Zukhra M.; Pashirova, Tatiana N.; Lyubina, Anna P.; Voloshina, Alexandra D.; Sapunova, Аnastasiia S.; Zakharova, L. Ya.; Миронов, В. Ф.

doi:10.1016/j.bmcl.2020.127234

Cited by 21 publications

(14 citation statements)

References 35 publications

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“…Recently, there has been growing interest in protonophoric uncouplers due to their antibacterial activity. − Bearing in mind that both protonophoric and detergent-like behavior of various small molecules may cause pronounced antibacterial action, − we studied the effect of the P 333 –P 888 series on the growth of Bacillus subtilis (Figure ). It is seen that P 444 –P 777 suppressed the bacterial growth at micromolar concentrations, whereas the effect of P 888 and P 333 was much weaker.…”

Section: Resultsmentioning

confidence: 99%

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents

et al. 2021

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Trialkyl phosphonium derivatives of vinyl-substituted p-chlorophenol were synthesized here by a recently developed method of preparing quaternary phosphonium salts from phosphine oxides using Grignard reagents. All the derivatives with a number (n) of carbon atoms in phosphonium alkyl substituents varying from 4 to 7 showed pronounced uncoupling activity in isolated rat liver mitochondria at micromolar concentrations, with a tripentyl derivative being the most effective both in accelerating respiration and causing membrane potential collapse, as well as in provoking mitochondrial swelling in a potassium-acetate medium. Remarkably, the trialkyl phosphonium derivatives with n from 4 to 7 also proved to be rather potent antibacterial agents. Methylation of the chlorophenol hydroxyl group suppressed the effects of P555 and P444 on the respiration and membrane potential of mitochondria but not those of P666, thereby suggesting a mechanistic difference in the mitochondrial uncoupling by these derivatives, which was predominantly protonophoric (carrier-like) in the case of P555 and P444 but detergent-like with P666. The latter was confirmed by the carboxyfluorescein leakage assay on model liposomal membranes.

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Section: Resultsmentioning

confidence: 99%

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents

et al. 2021

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“…[6] Our research groups have spent a decade on the construction of over 700 novel cationic disinfectant structures, endeavoring to identify structure-activity relationships (SAR) that can guide the development of novel, safe, and effective antimicrobials. [7][8] Recently, to broaden the structural variety of amphiphilic antiseptics more significantly, we expanded our interests to the production of trivalent sulfonium compounds (TSCs) [9][10][11][12] and to quaternary phosphonium compounds (QPCs), [13][14][15][16][17] hypothesizing that expanding beyond positively charged nitrogen species would afford novelty to challenge bacterial resistance mechanisms. [18] A recent publication from our groups reported that select QPC structures demonstrate significant broad-spectrum antimicrobial activity, and in some circumstances, surpass some of the most potent commercial QAC compounds while showing no capitulation to bacterial resistance mechanisms.…”

Section: Introductionmentioning

confidence: 99%

Rigidity‐Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria

et al. 2022

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Biscationic quaternary phosphonium compounds (bisQPCs) represent a promising class of antimicrobials, displaying potent activity against both Gram‐negative and Gram‐positive bacteria. In this study, we explored the effects of structural rigidity on the antimicrobial activity of QPC structures bearing a two‐carbon linker between phosphonium groups, testing against a panel of six bacteria, including multiple strains harboring known disinfectant resistance mechanisms. Using simple alkylation reactions, 21 novel compounds were prepared, although alkene isomerization as well as an alkyne reduction were observed during the respective syntheses. The resulting bisQPC compounds showed strong biological activity, but were hampered by diminished solubility of their iodide salts. One compound (P2P‐10,10 I) showed single‐digit micromolar activity against the entire panel of bacteria. Overall, intriguing biological activity was observed, with less rigid structures displaying better efficacy against Gram‐negative strains and more rigid structures demonstrating slightly increased efficacy against S. aureus strains.

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“…Quite recently, the effect of alkyl chain length on the bioactivity QPCs was reported by Tatarinov et al ., who synthesized a series of monocationic 2‐hydroxybenzylphosphonium salts ( 9 , Table 4). [29] QPCs 9 were ineffective against Gram‐negative bacterial strains, but showed low micromolar activity against two Gram‐positive strains. Optimal antibacterial activity was observed with 12‐carbon alkyl chain lengths.…”

Section: Quaternary Phosphonium Compounds As Small Molecule Antisepticsmentioning

confidence: 99%

Advancements in the Development of Non‐Nitrogen‐Based Amphiphilic Antiseptics to Overcome Pathogenic Bacterial Resistance

et al. 2020

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The prevalence of quaternary ammonium compounds (QACs) as common disinfecting agents for the past century has led bacteria to develop resistance to such compounds. Given the alarming increase in resistant strains, new strategies are required to combat this rise in resistance. Recent efforts to probe and combat bacterial resistance have focused on studies of multiQACs. Relatively unexplored, however, have been changes to the primary atom bearing positive charge in these antiseptics. Here we review the current state of the field of both phosphonium and sulfonium amphiphilic antiseptics, both of which hold promise as novel means to address bacterial resistance.

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Design and synthesis of amphiphilic 2-hydroxybenzylphosphonium salts with antimicrobial and antitumor dual action

Cited by 21 publications

References 35 publications

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents

Trialkyl(vinyl)phosphonium Chlorophenol Derivatives as Potent Mitochondrial Uncouplers and Antibacterial Agents

Rigidity‐Activity Relationships of bisQPC Scaffolds against Pathogenic Bacteria

Advancements in the Development of Non‐Nitrogen‐Based Amphiphilic Antiseptics to Overcome Pathogenic Bacterial Resistance

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