Fluorine Incorporation Research Articles

Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ

This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed.

Fluorinated Peptide Nucleic Acids with Fluoroacetyl Side Chain Bearing 5-(F/CF3)-Uracil: Synthesis and Cell Uptake Studies.

Fluorine incorporation into organic molecules imparts favorable physicochemical properties such as lipophilicity, solubility and metabolic stability necessary for drug action. Toward such applications using peptide nucleic acids (PNA), we herein report the chemical synthesis of fluorinated PNA monomers and biophysical studies of derived PNA oligomers containing fluorine in in the acetyl side chain (-CHF-CO-) bearing nucleobase uracil (5-F/5-CF3-U). The crystal structures of fluorinated racemic PNA monomers reveal interesting base pairing of enantiomers and packing arrangements directed by the chiral F substituent. Reverse phase HPLC show higher hydrophobicity of fluorinated PNA oligomers, dependent on the number and site of the fluorine substitution: fluorine on carbon adjacent to the carbonyl group induces higher lipophilicity than fluorine on nucleobase or in the backbone. The PNA oligomers containing fluorinated bases form hybrids with cDNA/RNA with slightly lower stability compared to that of unmodified aeg PNA, perhaps due to electronic effects. The uptake of fluorinated homooligomeric PNAs by HeLa cells was as facile as that of nonfluorinated PNA. In conjunction with our previous work on PNAs fluorinated in backbone and at N-terminus, it is evident that the fluorinated PNAs have potential to emerge as a new class of PNA analogues for applications in functional inhibition of RNA.

Planar microlens with front-face angle: design, fabrication, and characterization

This paper studies the effect of microlens front-face angle on the performance of an optical system consisting of a planar-graded refractive index (GRIN) lens pair facing each other separated by a free-space region. The planar silica microlens pairs are designed to facilitate low-loss optical signal propagation in the free-space region between the opposing optical waveguides. The planar lens is fabricated from a 38-μm-thick fluorine-doped silica layer on a silicon substrate. It has a parabolic refractive index profile in the vertical direction, which is achieved by controlled fluorine incorporation in the silica film to collimate the optical beam in the vertical direction. Horizontal beam collimation is achieved by incorporating a horizontal curvature at the front face of the lens defined by deep oxide etch. A generalized 3×3ABCDGH transformation matrix method has been derived to compute the coupling efficiency of such microlens pairs to take front-face angles that may be present due to fabrication variations or limitations and possible input/output optical fiber offset/tilt into considerations. Pairs of such planar GRIN lens with various free-space propagation distances between them ranging from 75 to 2500 μm and with front-face angles of 1.5 deg, 2 deg, and 4 deg have been fabricated and characterized. Beam propagation method simulations have been carried out to substantiate the theoretical and experimental results. The results indicate that the optical loss is reasonably low up to 1.5 deg of front-face angles and increases significantly with further increase in the front-face angle. Analysis shows that for a given system with specific microlens front-face angle, the optical loss can be significantly reduced by properly compensating the vertical position of the input and output fibers.

Effects of different plasma treatments of short fibers on the mechanical properties of polypropylene‐wood composites

In this work, a custom‐made reactor was developed to treat batches of short wood fibers with plasma. Three different plasma gases were tested: air, methane (CH4) and sulfur hexafluoride (SF6). The latter showed very promising results and was therefore used to prepare additional samples to determine the effects of plasma treatment and conditions on the wood fiber surface properties as well as the adhesion in a polypropylene matrix. As a result, composites made out of fibers plasma treated for 40 min at 60 W demonstrated an increase in the elastic modulus of more than 25%. Scanning electron microscope micrographs of the composites’ fracture surfaces indicated stronger interactions between treated fibers and the matrix. The incorporation of fluorine on treated fiber surfaces, mostly in covalent bonds with carbon, was clearly observed and analyzed by X‐ray photoelectron spectroscopy. The water contact angle on wood specimens treated under similar conditions displayed hydrophobic to superhydrophobic behavior, with contact angles exceeding 130°. POLYM. COMPOS., 39:1468–1479, 2018. © 2016 Society of Plastics Engineers

Quantitative Assessment of the Impact of Fluorine Substitution on P-Glycoprotein (P-gp) Mediated Efflux, Permeability, Lipophilicity, and Metabolic Stability.

Strategic replacement of one or more hydrogen atoms with fluorine atom(s) is a common tactic to improve potency at a given target and/or to modulate parameters such as metabolic stability and pKa. Molecular weight (MW) is a key parameter in design, and incorporation of fluorine is associated with a disproportionate increase in MW considering the van der Waals radius of fluorine versus hydrogen. Herein we examine a large compound data set to understand the effect of introducing fluorine on the risk of encountering P-glycoprotein mediated efflux (as measured by MDR efflux ratio), passive permeability, lipophilicity, and metabolic stability. Statistical modeling of the MDR ER data demonstrated that an increase in MW as a result of introducing fluorine atoms does not lead to higher risk of P-gp mediated efflux. Fluorine-corrected molecular weight (MWFC), where the molecular weight of fluorine has been subtracted, was found to be a more relevant descriptor.

Application of Fluorine Containing Bioactive Glass Nanoparticles in Dentin Hypersensitivity Treatment

The effect of Bioactive Glass on remineralization of dentin is the focus of the present study due to its excellent regenerative properties in mineralized tissues. It is known that the effect of Bioactive Glass can be enhanced at the nanoscale. In addition, the incorporation of Fluorine in the glass structure makes possible the formation of Fluorapatite (FAP). The aim of this study was to synthesize and characterize a new system of Fluorine containing Bioactive Glass Nanoparticles (FBGNP), and evaluate the potential for in vitro dentin remineralization by occlusion of dentinal tubules. The FBGNPs produced were uniform, with spherical shape and nanoscale size. Agglomeration or partial sinterization of the particulate system probably occurred after heat treatment. The results suggest the formation of FAP crystals embedded within the matrix of the Bioactive Glass. The gel containing FBGNP produced was effective in obliterating the dentinal tubules in vitro, showing that FBGNP is a potential material to be used for treatment of dentin hypersensitivity.

Evaluation of fluorinated biphenyl ether pro-drug scaffolds employing the chemical-microbial approach

Incorporation of fluorine in a drug can dramatically affect its metabolism and methods to assess the effect of fluorine substitution on drug metabolism are required for effective drug design. Employing a previously developed chemical-microbial method the metabolism of a series of fluorinated biphenyl ethers was determined. The substrates were synthesized via Ullmann-type condensation reactions between bromotoluene and fluorophenol. The ethers were incubated with the fungus Cunninghamella elegans, which oxidises xenobiotics in an analogous fashion to mammals, generating a number of hydroxylated biphenyl ethers and acids. The propensity of the fluorinated ring to be hydroxylated depended upon the position of the fluorine atom, and the oxidation of the methyl group was observed when it was meta to the oxygen. The experiments demonstrate the applicability of the method to rapidly determine the effect of fluorine substitution on CYP-catalysed biotransformation of pro-drug molecules.

Organic Multilevel Memory Devices of Long‐Term Environmental Stability via Incorporation of Fluorine

Organic resistive memory devices have been considered as potential candidates for next‐generation, non‐volatile memories. As prerequisites for real applications such memory devices would need to attain a high storage density, low power consumption, and, especially, long‐term stability. Although extensive research has been carried out these issues have thus far not been resolved in a satisfactory manner. In this work, two phenothiazine‐cored, cyano‐substituted diphenylethene derivatives with trifluoromethyl and nitro‐groups (PTZ‐CF3 and PTZ‐NO2) are presented and the performance of electroresistive memory devices based on these two molecules is investigated. Both molecules can realize ternary memory data storage with ternary device yields as high as 70%. In addition, PTZ‐CF3‐based devices exhibit a long‐term stability (up to three months), lower operating voltage (−1.01/−2.42 V), and higher ON/OFF ratios (>104 and 103) compared to those based on PTZ‐NO2. Such superior performance can be attributed to the introduced trifluoromethyl group, which leads to a better solubility, film‐forming ability, and hydrophobicity. These results may serve as a guide to improve the performance and promote the development of organic memories.

The chemical composition of uranospathite, arsenurano-spathite, and associated minerals revisited: the peculiarity of fluorine incorporation in autunite group minerals

The chemical composition of uranospathite, arsenurano-spathite, and associated minerals revisited: the peculiarity of fluorine incorporation in autunite group minerals

The chemical composition of uranospathite, arsenuranospathite, and associated minerals revisited: the peculiarity of fluorine incorporation in autunite group minerals

The chemical composition of uranospathite, arsenuranospathite, and associated minerals revisited: the peculiarity of fluorine incorporation in autunite group minerals

Passivation of oxide traps and interface states in GaAs metal-oxide-semiconductor capacitor by LaTaON passivation layer and fluorine incorporation

GaAs metal-oxide-semiconductor capacitor with TaYON/LaTaON gate-oxide stack and fluorine-plasma treatment is fabricated and compared with its counterparts without the LaTaON passivation interlayer or the fluorine treatment. Experimental results show that the sample exhibits better characteristics: low interface-state density (8 × 1011 cm−2/eV), small flatband voltage (0.69 V), good capacitance-voltage behavior, small frequency dispersion, and small gate leakage current (6.35 × 10−6 A/cm2 at Vfb + 1 V). These should be attributed to the suppressed growth of unstable Ga and As oxides on the GaAs surface during gate-oxide annealing by the LaTaON interlayer and fluorine incorporation, and the passivating effects of fluorine atoms on the acceptor-like interface and near-interface traps.

Investigation of low-frequency noise of 28-nm technology process of high-k/metal gate p-MOSFETs with fluorine incorporation

In this study, the properties of dielectric traps by the impact of Fluorine (F) implantation on 1/f noise and the random telegraph noise (RTN) of high-k/metal gate (HK/MG) p-type metal–oxide–semiconductor field-effect transistors (pMOSFETs) were investigated. The incorporation of F has been identified as an effective method to passivate oxygen vacancies, defect sites, and reduce the gate leakage current in pMOSFETs. Compared with a control device, the F-implanted HK/MG devices show that the trap positions were closer to the SiO2 interfacial layer (IL)/Si channel. Furthermore, we found that F implantation could result in a smaller tunneling attenuation length (λ) and smaller slow oxide interface trap density (Nt).

Preparation and characterization of fluorinated acrylic pressure sensitive adhesives for low surface energy substrates

Abstract In this work, a series of PSAs with various fluorinated groups were synthesized using 2,2,3,4,4,4-hexafluorobutyl acrylate (F6BA) via solution polymerization. Compared to existing PSAs, fluorinated acrylic PSAs exhibited excellent performance in terms of the adhesiveness to the low surface energy materials. F6BA played a positive role in heat resistance of PSAs, resulting from the improvement of decomposition temperatures of PSAs substantially due to the addition of fluorinated groups. FT-IR and DSC results indicated that fluorinated groups were introduced to the structure of copolymer successfully and all the monomers were well copolymerized. Furthermore, it was confirmed that the incorporation of fluorine improved wettability of PSAs effectively and extended protective property of PSAs against the water corrosion.

Passivation of oxide traps in gallium arsenide (semiconductor) metal-oxide-semiconductor capacitor with high-k dielectric by using fluorine incorporation

Gallium arsenide (semiconductor) (GaAs) metal-oxide-semiconductor capacitors with fluorine-incorporated TaHfON as gate dielectric are fabricated by pre- or postdeposition fluorine plasma treatment and their electrical and physical properties are compared with a control sample without the treatment. Among the three devices, the one with postdeposition fluorine treatment exhibits better characteristics: low oxide-charge density (−3.5 × 1012 cm−2), low interface-state density (2.2 × 1012 cm−2eV−1), small flatband voltage (0.7 V), small hysteresis (45 mV), and good capacitance–voltage behavior. These should be attributed to (1) the passivating effects of fluorine atoms on the acceptorlike interface and near-interface traps, and (2) fluorine-induced suppressed growth of unstable Ga and As oxides on the GaAs substrate during postdeposition annealing.

Applications of Fluorine in Medicinal Chemistry.

The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.

ChemInform Abstract: Selective Incorporation of Fluorine in Pyrazoles

AbstractReview: [103 refs.

Incorporation of Fluorine onto Different Positions of Phenyl Substituted Benzo[1,2-b:4,5-b′]dithiophene Unit: Influence on Photovoltaic Properties

We have designed and synthesized two low bandgap conjugated copolymers containing alternating meta-fluoro-p-alkoxyphenyl- (m-FPO-) or p-fluoro-m-alkoxyphenyl- (p-FPO-) substituted benzodithiophenes-co-benzooxadiazole (BO), named PBO-m-FPO and PBO-p-FPO. The properties, including UV–vis absorption, charge mobility and photovoltaic performance of the two polymers have been intensively investigated. The results indicated that the introduction of fluorine atom at m, p positions of phenyl substituted benzodithiophene unit hardly affected their absorption spectra and highest occupied molecular orbital (HOMO) level. However, the two polymers showed different photovoltaic properties. Power conversion efficiencies (PCEs) based on the device structure of ITO/PEDOT:PSS/polymer:PC71BM/Ca/Al demonstrated a large distinction (5.9% for PBO-m-FPO vs 2.8% for PBO-p-FPO) at optimal weight ratio. When replacing the Ca layer with zirconium acetylacetonate (ZrAcac), using 3% 1,8-diiodooctane (DIO) as the active layer additive, the PCEs of PBO-m-FPO and PBO-p-FPO increased by 36% (8.0% vs 5.9%) and 85% (5.1% vs 2.8%), respectively. The active layer’s mobilities, morphology and molecular packing resulted in a significant difference in short-circuit current density (Jsc) and fill factor (FF).

Synthesis of fluorinated oxygen- and sulfur-containing heteroaromatics

The incorporation of fluorine into a target molecule may have a considerable impact on its reactivity, selectivity, biological activity and physical properties. This is especially true in medicinal chemistry where fluorine is often employed as a bioisostere of hydrogen and where many important drug compounds also feature heteroaromatic rings. This work complements existing reviews on the synthesis of fluorinated, aromatic heterocycles, with a focus on less common oxygen-containing heteroaromatics as well as their sulfur-based analogues.

Recent advances in green fluorine chemistry

Recent advances in green fluorine chemistry Yuwen Zeng, Jinbo HuKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, People’s Republic of ChinaAbstract: Fluorinated compounds are intriguing for the development of pharmaceuticals, agrochemicals, and materials, and thus, much effort has been exerted to develop more general and efficient approaches for introducing fluorine atom(s) or fluoroalkyl group(s) into organic molecules. Although many traditional methods usually cannot satisfy the simplicity and cost efficiency for industrial production and laboratorial synthesis, significant progress in green fluorine chemistry has been made in recent years, allowing efficient incorporation of fluorine into complex organic molecules. The main purpose of this review is to describe recent advances in organofluorine chemistry, with an emphasis on generality, selectivity, and environmental friendliness of related methods.Keywords: green chemistry, organofluorine chemistry, fluorination, perfluoroalkylation, trifluoromethylation

Investigation and conformational analysis of fluorinated nucleoside antibiotics targeting siderophore biosynthesis.

Antibiotic resistance represents one of the greatest threats to public health. The adenylation inhibitor 5'-O-[N-(salicyl)sulfamoyl]adenosine (SAL-AMS) is the archetype for a new class of nucleoside antibiotics that target iron acquisition in pathogenic microorganisms and is especially effective against Mycobacterium tuberculosis, the causative agent of tuberculosis. Strategic incorporation of fluorine at the 2' and 3' positions of the nucleoside was performed by direct fluorination to enhance activity and improve drug disposition properties. The resulting SAL-AMS analogues were comprehensively assessed for biochemical potency, whole-cell antitubercular activity, and in vivo pharmacokinetic parameters. Conformational analysis suggested a strong preference of fluorinated sugar rings for either a 2'-endo, 3'-exo (South), or a 3'-endo,2'-exo (North) conformation. The structure-activity relationships revealed a strong conformational bias for the C3'-endo conformation to maintain potent biochemical and whole-cell activity, whereas improved pharmacokinetic properties were associated with the C2'-endo conformation.