The Role of Fluorine in Glycomimetic Drug Design

Hevey, Rachel

doi:10.1002/chem.202003135

Cited by 60 publications

(57 citation statements)

References 196 publications

(171 reference statements)

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“…The C-F bond has been used as a bioisostere for a number of functional groups, including C-H, C-OH, C=O, and CN [ 27 ]. The high dissociation energy (105.4 kcal/mol) of C-F bond is difficult to break and therefore less prone for metabolic transformation [ 28 ]. The incorporation of fluorine atoms or fluorinated functional group has become a growing trend in drug development, as it can be used to improve activity, improve bioavailability, and slow metabolic degradation.…”

Section: Introductionmentioning

confidence: 99%

Bio-evaluation of fluoro and trifluoromethyl-substituted salicylanilides against multidrug-resistant S. aureus

et al. 2021

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Methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus (VRSA) are primary causes of skin and soft tissue infections worldwide. To address the emergency caused due to increasing multidrug-resistant (MDR) bacterial infections, a series of novel fluoro and trifluoromethyl-substituted salicylanilide derivatives were synthesized and their antimicrobial activity was investigated. MIC data reveal that the compounds inhibited S. aureus specifically (MIC 0.25–64 µg/mL). The in vitro cytotoxicity of compounds with MIC < 1 µg/mL against Vero cells led to identification of four compounds ( 20 , 22 , 24 and 25 ) with selectivity index above 10. These four compounds were tested against MDR S. aureus panel. Remarkably, 5-chloro- N -(4’-bromo-3’-trifluoromethylphenyl)-2-hydroxybenzamide ( 22 ) demonstrated excellent activity against nine MRSA and three VRSA strains with MIC 0.031–0.062 µg/mL, which is significantly better than the control drugs methicillin and vancomycin. The comparative time–kill kinetic experiment revealed that the effect of bacterial killing of 22 is comparable with vancomycin. Compound 22 did not synergize with or antagonize any FDA-approved antibiotic and reduced pre-formed S. aureus biofilm better than vancomycin. Overall, study suggested that 22 could be further developed as a potent anti-staphylococcal therapeutic.

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Section: Introductionmentioning

confidence: 99%

Bio-evaluation of fluoro and trifluoromethyl-substituted salicylanilides against multidrug-resistant S. aureus

et al. 2021

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“…The small size of fluorine is important in the use of fluorine in drug development, since fluorine is not too much larger than a hydrogen substituent and can often substitute sterically without compromising target binding. Such a substitution can serve to substantially moderate drug clearance, an important consideration in drug efficacy (Meanwell, 2018 ; Al‐Harthy et al ., 2020 ; Hevey, 2021 ; Richardson, 2021 ). The lower reactivity of designed organofluorine drugs with Phase I drug metabolism enzymes, typically oxygenases, is paralleled by a typically lesser biodegradation by bacterial oxygenases that act on hydrocarbon substrates in the environment.…”

Section: Fluorine Chemistry Is Different From Other Halogens Fluorine...mentioning

confidence: 99%

Nothing lasts forever: understanding microbial biodegradation of polyfluorinated compounds and perfluorinated alkyl substances

Wackett

2021

Microbial Biotechnology

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Poly-and perfluorinated chemicals, including perfluorinated alkyl substances (PFAS), are pervasive in today's society, with a negative impact on human and ecosystem health continually emerging. These chemicals are now subject to strict government regulations, leading to costly environmental remediation efforts. Commercial polyfluorinated compounds have been called 'forever chemicals' due to their strong resistance to biological and chemical degradation. Environmental cleanup by bioremediation is not considered practical currently. Implementation of bioremediation will require uncovering and understanding the rare microbial successes in degrading these compounds. This review discusses the underlying reasons why microbial degradation of heavily fluorinated compounds is rare. Fluorinated and chlorinated compounds are very different with respect to chemistry and microbial physiology. Moreover, the end product of biodegradation, fluoride, is much more toxic than chloride. It is imperative to understand these limitations, and elucidate physiological mechanisms of defluorination, in order to better discover, study, and engineer bacteria that can efficiently degrade polyfluorinated compounds.

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“…26 A variety of functional groups, including C-H, C-OH, C=O, and C≡N, have utilized the C-F bond as a bioisostere. 27 However, it is difficult to generalize the relative ability of fluorine to act similar to a hydrogen or hydroxy group, and different factors must be considered in each case. The van der Waals radius of fluorine (1.47 Å) lies between that of oxygen (1.57 Å) and hydrogen (1.2 Å) and as it is the element with the highest electronegativity, the C-F bond is almost identical to C-OH in terms of bond length and polarity.…”

Section: Introductionmentioning

confidence: 99%

Hydration Dynamics and IR Spectroscopy of 4-Fluorophenol

Salehi¹,

Käser²,

Töpfer³

et al. 2022

Preprint

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Halogenated groups are relevant in pharmaceutical applications and potentially useful spectroscopic probes for infrared spectroscopy. In this work, the structural dynamics and infrared spectroscopy of para-fluorophenol (F-PhOH) and phenol (PhOH) is investigated in the gas phase and in water using a combination of experiment and molecular dynamics (MD) simulations. The gas phase and solvent dynamics around F-PhOH and PhOH is characterized from atomistic simulations using empirical energy functions with point charges or multipoles for the electrostatics, Machine-Learning (ML) based parametrization and with full ab initio (QM) and mixed Quantum Mechanical/Molecular Mechanics (QM/MM) simulations with a particular focus on the CF-and OH-stretch region. The CF-stretch band is heavily mixed with other modes whereas the OH-stretch in solution displays a characteristic high-frequency peak around 3600 cm −1 most likely associated with the -OH group of PhOH and F-PhOH together with a characteristic progression below 3000 cm −1 due to coupling with water modes which is also reproduced by several of the simulations. Solvent and radial distribution functions indicate that the CF-site is largely hydrophobic except for simulations using point charges which renders them unsuited for correctly describing hydration and dynamics around fluorinated sites.

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The Role of Fluorine in Glycomimetic Drug Design

Cited by 60 publications

References 196 publications

Bio-evaluation of fluoro and trifluoromethyl-substituted salicylanilides against multidrug-resistant S. aureus

Bio-evaluation of fluoro and trifluoromethyl-substituted salicylanilides against multidrug-resistant S. aureus

Nothing lasts forever: understanding microbial biodegradation of polyfluorinated compounds and perfluorinated alkyl substances

Hydration Dynamics and IR Spectroscopy of 4-Fluorophenol

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