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

Terekhova, Natalia V.; Khailova, Ljudmila S.; Rokitskaya, Tatyana I.; Nazarov, Pavel A.; Islamov, Daut R.; Usachev, Konstantin S.; Татаринов, Д. А.; Миронов, В. Ф.; Kotova, Еlena А.; Antonenko, Yuri N.

doi:10.1021/acsomega.1c02909

Cited by 12 publications

(9 citation statements)

References 62 publications

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“…Strictly speaking, these compounds are not aromatic; in addition, their ability to become deprotonated in an aqueous medium also raises serious questions. Recent studies have identified cationic [ 19 , 20 , 21 ] and zwitterionic protonophores [ 22 , 23 , 24 ].…”

Section: Protonophores and Lipid Membranesmentioning

confidence: 99%

Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action

Kotova

Antonenko

2022

Acta Naturae

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Protonophores are compounds capable of electrogenic transport of protons across membranes. Protonophores have been intensively studied over the past 50 years owing to their ability to uncouple oxidation and phosphorylation in mitochondria and chloroplasts. The action mechanism of classical uncouplers, such as DNP and CCCP, in mitochondria is believed to be related to their protonophoric activity; i.e., their ability to transfer protons across the lipid part of the mitochondrial membrane. Given the recently revealed deviations in the correlation between the protonophoric activity of some uncouplers and their ability to stimulate mitochondrial respiration, this review addresses the involvement of some proteins of the inner mitochondrial membrane, such as the ATP/ADP antiporter, dicarboxylate carrier, and ATPase, in the uncoupling process. However, these deviations do not contradict the Mitchell theory but point to a more complex nature of the interaction of DNP, CCCP, and other uncouplers with mitochondrial membranes. Therefore, a detailed investigation of the action mechanism of uncouplers is required for a more successful pharmacological use, including their antibacterial, antiviral, anticancer, as well as cardio-, neuro-, and nephroprotective effects.

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Section: Protonophores and Lipid Membranesmentioning

confidence: 99%

Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action

Kotova

Antonenko

2022

Acta Naturae

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“…46 Antibacterial Activity of SF-C n -TPP. Like other zwitterionic uncouplers, 35,39,47 SF-C n -TPP (n = 4, 5, 10) exhibited antibacterial activity with Gram-positive species. In particular, the growth of Bacillus subtilis was inhibited at micromolar concentrations of these compounds (Table 1).…”

Section: Direct Measurements Of Proton Transport Induction By Sf-c N ...mentioning

confidence: 99%

Synthesis of Triphenylphosphonium-Linked Derivative of 3,5-Ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847) via Knoevenagel Reaction Yields an Effective Mitochondria-Targeted Protonophoric Uncoupler

Kirsanov,

Khailova,

Rokitskaya

et al. 2024

ACS Omega

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Mitochondrial uncouplers are actively sought as potential therapeutics. Here, we report the first successful synthesis of mitochondria-targeted derivatives of the highly potent uncoupler 3,5-ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847), bearing a cationic alkyl(triphenyl)phosphonium (TPP) group. As a key step of the synthesis, we used condensation of a ketophenol with malononitrile via the Knoevenagel reaction. SF-C 5 -TPP with a pentamethylene linker between SF6847 and TPP, stimulating respiration and collapsing membrane potential of rat liver mitochondria at submicromolar concentrations, proved to be the most effective uncoupler of the series. SF-C 5 -TPP showed pronounced protonophoric activity on a model planar bilayer lipid membrane. Importantly, SF-C 5 -TPP exhibited rather low toxicity in fibroblast cell culture, causing mitochondrial depolarization in cells at concentrations that only slightly affected cell viability. SF-C 5 -TPP was more effective in decreasing the mitochondrial membrane potential in the cell culture than SF6847, in contrast to the case of isolated mitochondria. Like other zwitterionic uncouplers, SF-C 5 -TPP inhibited the growth of Bacillus subtilis in the micromolar concentration range.

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“…This means that the activity only increases to a certain tail length and then decreases. The cut-off effect of the membrane active compounds (which penetrate to the membrane and disrupt its architecture) has been well documented [14,19,20,[36][37][38][39][40][41][42][43][44].…”

Section: Chemistrymentioning

confidence: 99%

“…It can only be speculated whether the different courses of dependences of bactericidal activities against S. aureus ATCC 29213/MRSA SA 3202 (MRSA3) from isolates MRSA1/MRSA2 could be due to their differences in the composition of bacterial membranes [55][56][57][58]. The effect of changing the length of the hydrocarbon tail affecting the extent of antimicrobial activity of the compounds has been discussed (e.g., [36,37,[39][40][41][42][43][44]59,60]). The decrease in biological activity at a higher chain length as a cut-off effect is discussed above.…”

Section: Structure-activity Relationshipsmentioning

confidence: 99%

Antistaphylococcal Activities and ADME-Related Properties of Chlorinated Arylcarbamoylnaphthalenylcarbamates

et al. 2022

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Pattern 1-hydroxy-N-(2,4,5-trichlorophenyl)-2-naphthamide and the thirteen original carbamates derived from it were prepared and characterized. All the compounds were tested against Staphylococcus aureus ATCC 29213 as a reference and quality control strain and in addition against three clinical isolates of methicillin-resistant S. aureus (MRSA). Moreover, the compounds were evaluated against Enterococcus faecalis ATCC 29212, and preliminary in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line (THP-1). The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. While pattern anilide had no antibacterial activity, the prepared carbamates demonstrated high antistaphylococcal activity comparable to the used standards (ampicillin and ciprofloxacin), which unfortunately were ineffective against E. feacalis. 2-[(2,4,5-Trichlorophenyl)carba- moyl]naphthalen-1-yl ethylcarbamate (2) and 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl butylcarbamate (4) expressed the nanomolar minimum inhibitory concentrations (MICs 0.018–0.064 μM) against S. aureus and at least two other MRSA isolates. Microbicidal effects based on the minimum bactericidal concentrations (MBCs) against all the tested staphylococci were found for nine carbamates, while 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl heptylcarbamate (7) and 2-[(2,4,5-trichlorophenyl)carbamoyl]naphthalen-1-yl (4-phenylbutyl)carbamate (14) demonstrated MBCs in the range of 0.124–0.461 μM. The selectivity index (SI) for most investigated carbamates was >20 and for some derivatives even >100. The performed tests did not show an effect on the damage to the bacterial membrane, while the compounds were able to inhibit the respiratory chain of S. aureus.

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

Cited by 12 publications

References 62 publications

Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action

Fifty Years of Research on Protonophores: Mitochondrial Uncoupling As a Basis for Therapeutic Action

Synthesis of Triphenylphosphonium-Linked Derivative of 3,5-Ditert-butyl-4-hydroxybenzylidene-malononitrile (SF6847) via Knoevenagel Reaction Yields an Effective Mitochondria-Targeted Protonophoric Uncoupler

Antistaphylococcal Activities and ADME-Related Properties of Chlorinated Arylcarbamoylnaphthalenylcarbamates

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