Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections

Shinya, Susumu; Kawai, Kentaro; Kobayashi, Naoki; Karuo, Yukiko; Tarui, Atsushi; Sato, Kazuyuki; Otsuka, Masato; Omote, Masaaki

doi:10.1016/j.bmc.2022.117042

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…Fluorophenyl substituents play an important role in novel antibiotic resistance and cancer therapy drugs, − in addition to improving ligand affinities compared to phenyl substituents. , These drugs have been shown to have different efficacies when the fluorine is located at different positions on the phenyl substituents . While the structures of fluorophenyl radical reactants can be controlled with leaving groups at the targeted radical position relative to the C–F positions, carbanions may offer another tool in the synthetic toolbox, and our results suggest the potential utility of fluorophenide anions in these syntheses.…”

Section: Introductionmentioning

confidence: 77%

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)

McGinnis,

McGee,

Jarrold

2024

J. Am. Chem. Soc.

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Di-, tri-, and tetrafluorophenyl radicals each have three regioisomers, several of which can form multiple distinct radical structures. We present the photoelectron spectra of the di-, tri-, and tetrafluorophenide regioisomer anions generated from their associated fluorobenzene precursors. By comparing the spectra to the results of density functional theory calculations, we determine that in cases where more than one possible radical isomer is possible for a given regioisomer (radicals formed from 1,2-difluorobenzene, 1,3-difluorobenzene, 1,2,3-trifluorobenzene, and 1,2,4-trifluorobenzene) the most stable anion corresponds to a less stable neutral, suggesting that the reactive C-center on these fluorine-substituted phenyl groups can be controlled by charge state. Full analyses of the spectra and computational results yield further insights into the differences between the electronic and molecular structures of the fluorophenyl radicals and their associated anions.

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Section: Introductionmentioning

confidence: 77%

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)

McGinnis,

McGee,

Jarrold

2024

J. Am. Chem. Soc.

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“…Moreover, the group of Kawai and Kobayashi evaluated the optimization of the chemical structure of a bacterial-selective multidrug and toxin extrusion (MATE) inhibitor 109 in order to improve its activity (EC50 >30 μM). 50 Structural modifications on each part of this compound (aromatic, linker and guanidine parts) have been performed and the efficacy of the corresponding derivatives has been evaluated. Indeed, the presence of the pentafluorosulfanyl group on the aromatic part improved remarkably the activity of the MATE-type inhibitor 110 (figure 12) against HmrM-expressing strain when co-administrated with norfloxacin (EC50 = 1.8 μM).…”

Section: Template For Synthesis Thiemementioning

confidence: 99%

Recent Advances in the Chemistry and Application of SF5-Compounds

Bizet,

Abd El Sater,

Popek

et al. 2024

Synthesis

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This review article outlines the literature covering last three years on the recent developments of the SF5 chemistry. Recent synthesis methodologies of SF5-containing building blocks are reported. These methods include the synthesis of SF5Cl, its use in pentafluorosulfanylation reactions, and oxidative fluorination reactions. Moreover, the reactivity of SF5-alkynes as versatile platform to access new SF5-compounds is described. Finally, effect of SF5 moiety is highlighted according to its application in different fields such as biological/medicinal chemistry, catalysis and material sciences.

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“…Yet, among current preclinical anti-bacterial approaches few directly address transporters, including PHT-427 for Gram-positive and Gram-negative ferrous iron uptake 4 or GW3965·HCl only for Gram-positive ferrous iron uptake 5 as well as fluorophenylalkyl-substituted cyanoguanidine derivatives 6 and others in early development 7 that suppress drug efflux. None directly inhibit more than one transporter.…”

Section: Introductionmentioning

confidence: 99%

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

Sharifian Gh.,

Norouzi,

Sorci

et al. 2024

Preprint

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Discovering new bacterial signaling pathways offers unique antibiotic strategies. Here, through an unbiased resistance screen of 3,884 gene knockout strains, we uncovered a previously unknown non-lytic bactericidal mechanism that sequentially couples three transporters and downstream transcription to lethally suppress respiration of the highly virulent P. aeruginosa strain PA14 - one of three species on the WHO's 'Priority 1: Critical' list. By targeting outer membrane YaiW, cationic lacritin peptide 'N-104' translocates into the periplasm where it ligates outer loops 4 and 2 of the inner membrane transporters FeoB and PotH, respectively, to suppress both ferrous iron and polyamine uptake. This broadly shuts down transcription of many biofilm-associated genes, including ferrous iron-dependent TauD and ExbB1. The mechanism is innate to the surface of the eye and is enhanced by synergistic coupling with thrombin peptide GKY20. This is the first example of an inhibitor of multiple bacterial transporters.

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Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections

Cited by 3 publications

References 31 publications

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)

Recent Advances in the Chemistry and Application of SF5-Compounds

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

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Fluorophenylalkyl-substituted cyanoguanidine derivatives as bacteria-selective MATE transporter inhibitors for the treatment of antibiotic-resistant infections

Cited by 3 publications

References 31 publications

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, •C6H5–xFx (2 ≤ x ≤ 4)

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, •C6H5–xFx (2 ≤ x ≤ 4)

Recent Advances in the Chemistry and Application of SF5-Compounds

Targeting Iron - Respiratory Reciprocity Promotes Bacterial Death

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Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)

Isomer-Dependent Electron Affinities of Fluorophenyl Radicals, ^•C₆H_5–xF_x (2 ≤ x ≤ 4)