Fluorine-containing Derivatives Research Articles

Development of Approaches for Obtaining Fluorine-Containing Derivatives of Boronated Amidines Based on the closo-Dodecaborate Anion

Development of Approaches for Obtaining Fluorine-Containing Derivatives of Boronated Amidines Based on the closo-Dodecaborate Anion

Introduction of Fluorine into Antitumor-Active Dinuclear Platinum(II) Complexes Leads to Modulation of In Vivo Antitumor Activity in Mice.

Tetrazolato-bridged dinuclear platinum(II) complexes ([{cis-Pt(NH3)2}2(μ-OH)(μ-5-R-tetrazolato-N2,N3)]2+; tetrazolato-bridged complexes) show remarkable cytotoxic effects in vitro and antitumor activity in vivo. Here, we examined the structure-activity relationship of a series of fluorine-containing derivatives (R = CFH2, CF2H, or CF3), focusing on their lipophilicity, cellular accumulation, cytotoxicity, interactions with a nucleobase and double-stranded deoxyribonucleic acid, and in vivo antitumor efficacy. Fluorination had a little effect on the properties of the derivatives in vitro; however, marked differences in in vitro cytotoxicity and in vivo tumor growth inhibition activity were observed. In BALB/c mice bearing colon-26 tumors, the antitumor efficacies of the derivatives were markedly altered, even by changing the number of fluorine atoms by one. In addition, one derivative, [{cis-Pt(NH3)2}2(μ-OH)(μ-5-difluoromethyltetrazolato-N2,N3)](NO3)2, showed a significantly higher antitumor efficacy compared with oxaliplatin, a current first-line drug and the only platinum-based drug approved for the treatment of colon cancer. Together, the present results indicate that introducing fluorine into tetrazolato-bridged complexes may be useful for modulating in vivo activities.

Synthesis of Fluorine-Containing Analogues of Purine Deoxynucleosides: Optimization of Enzymatic Transglycosylation Conditions

In this work, a comparative analysis of the conditions of transglycosylation reactions catalyzed by E. coli nucleoside phosphorylases was carried out, and the optimal conditions for the formation of various nucleosides were determined. Under the optimized conditions of transglycosylation reaction, fluorine-containing derivatives of N6-benzyl-2'-deoxyadenosine, potential inhibitors of replication of enteroviruses in a cell, were obtained starting from the corresponding ribonucleosides.

COMPARISON OF FUNGICIDAL ACTIVITY OF FLUCONAZOLE AND FLUORINE-CONTAINING 1,2,4-TRIAZOLES VIA IN VITRO AND IN SILICO METHODS

Diseases caused by fungal infections affect millions of people and plants every year. Candida albicans is one of the most common fungi, causing a variety of fungal diseases that are life-threatening, especially for cancer patients and HIV-positive people. At the same time, drug therapy aimed at treating these diseases is limited by the small number of drugs used. Among them, one of the most commonly used both in human treatment and as part of the active components of agricultural fungicides is fluconazole - a drug that combines the nucleus of 1,2,4-triazole and fluorine atoms.
 Previously, we have investigated the antifungal activity of condensed salts of thiazolo[3,2-b][1,2,4]triazole obtained by electrophilic intramolecular cyclization, bis-triazoles and their alkylated derivatives, and proved the feasibility of their use as bactericides and fungicides.
 The aim of this work is to investigate the interaction of fluconazole and synthesized fluorine-containing compounds of class 1,2,4-triazole with the enzyme "EC 2.2.1.6 Acetolactate synthase" in the crystal structure of Candida albicans and to evaluate the possible use of the obtained substances as fungicides.
 In the current study, we investigated the antifungal action of fluorine-containing derivatives of 1,2,4-triazole-3-thione. Molecular docking was performed for the compounds with the highest fungicidal activity and the preparation of fluconazole for the enzyme "EC 2.2.1.6 Acetolactate synthase" Candida albicans. The results showed that one of the tested substances showed a higher affinity for binding in the active site of the enzyme than fluconazole. Therefore, the test substances are promising antifungal agents.
 Keywords: 1,2,4-triazole-3-thione; fungicidal activity; molecular docking; Candida albicans.

Directed synthesis of copolymers based on fluorine-containing (meth)acrylate derivatives

Directed synthesis of copolymers based on fluorine-containing (meth)acrylate derivatives

Directed synthesis of copolymers based on fluorine-containing styrene derivatives

Directed synthesis of copolymers based on fluorine-containing styrene derivatives

Design, synthesis and biological evaluation of Tozadenant analogues as adenosine A2A receptor ligands.

With the aim to obtain potent adenosine A2A receptor (A2AR) ligands, a series of eighteen derivatives of 4-hydroxy-N-(4-methoxy-7-morpholin-4-yl-1,3-benzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide (SYN-115, Tozadenant) were designed and synthesized. The target compounds were obtained by a chemical building block principle that involved reaction of the appropriate aminobenzothiazole phenyl carbamates with either commercially available or readily synthesized functionalized piperidines. Their affinity and subtype selectivity with regard to human adenosine A1-and A2A receptors were determined using radioligand binding assays. Ki values for human A2AR ranged from 2.4 to 38nM, with more than 120-fold selectivity over A1 receptors for all evaluated compounds except 13k which had a Ki of 361nM and 18-fold selectivity. The most potent fluorine-containing derivatives 13e, 13g and 13l exhibited Ki values of 4.9nM, 3.6nM and 2.8nM for the human A2AR. Interestingly, the corresponding values for rat A2AR were found to be four to five times higher. Their binding to A2AR was further confirmed by radiolabeling with 18F and invitro autoradiography in rat brain slices, which showed almost exclusive striatal binding and complete displacement by the A2AR antagonist ZM 241385. We conclude that these compounds represent potential candidates for the visualization of the A2A receptor and open pathways to novel therapeutic treatments of neurodegenerative disorders or cancer.

SYNTHESIS AND BROMINATION OF PROPARGYLIC TRIFLUOROUTIC ACID AMIDE

Carboxylic acid amides are convenient reagents for organic synthesis, and are promising building blocks for obtaining a large number of acyclic and heterocyclic compounds.Among the various aliphatic, aromatic and heterocyclic amides, fluorine-containing derivatives are the least studied. The presence of a carbonyl group, a fluoroalkyl substituent and an alkyl-substituted amino functional groups determines the variety of transformations for this class of compounds. The introduction of an unsaturated alkyl substituent to the amide nitrogen atom and the presence of an additional nucleophilic center of the oxygen or nitrogen atom makes such amides promising for the study of their reactions with electrophilic reagents.The aim of this work is the synthesis of propargyl trifluoroacetic acid amide and the study of its interaction with bromine.Trifluoroacetic acid propargylamide was prepared from trifluoroacetic acid ethyl ester and propargylamine in tetrahydrofuran medium, its structure was confirmed by NMR1H and NMR19F spectra.It is known from the literature sources that the presence of a multiple bond and an additional intramolecular nucleophilic center in propargyl amines and amides creates the pre-conditions for the cyclization reaction under the action of halogen-containing electrophilic reagents. Such structural features are also characteristic for N-propargyltrifluoroacetamide, namely the multiple bond of the propargyl moiety and additional intramolecular nucleophilic centers of nitrogen and oxygen atoms. Under the action of bromine as an electrophilic reagent on N-propargyltrifluoroacetamide, the formation of both the coupling product and the cyclization with the formation of azetidine, oxazoline or oxazine heterocycles is possible.The bromination reaction of N-propargyltrifluoroacetamide was performed in dichloromethane with an equimolar amount of reagents in the presence of potash. According to the spectral data, the coupling product N- (2,3-dibromoprop-2-en-1-yl) trifluoroacetamide is formed, which is confirmed by the NMR1H and NMR19F spectra. The absence of the cyclization process can be explained via the lower nucleophilicity of the oxygen atom compared to sulfur.

Design, synthesis and antiproliferative activity evaluation of fluorine-containing chalcone derivatives

A series of new chalcones containing fluoro atom at B ring have been designed, synthesized, and evaluated to be antiproliferative activity against a panel of human tumor cell lines. Some of the analogs (8, 9, 12, 45, 46 and 48) displayed powerful antiproliferative effects to certain human tumor cells, but all of them were devoid of any cytotoxicity towards the normal HEK 293. Acridine orange staining data supported that the cytotoxic and antiproliferative effects of the synthesized analogs on tumor cells are mediated through apoptosis. The compounds 12 and 46 manifested concentration-dependent antiproliferative activity in human hepatocellular carcinoma cell lines using an xCELLigence assay. The structures and antiproliferative activity relationship were further supported by in silico molecular docking study of the compounds against tubulin protein which suggests our compounds interference to cell division. Communicated by Ramaswamy H. Sarma

Synthesis and Structure of Fluorinated (Benzo[d]imidazol-2-yl)methanols: Bench Compounds for Diverse Applications

A simple and general approach to the synthesis (from commercial precursors) of eight out of nine possible (benzo[d]imidazol-2-yl)methanols fluorinated on the benzene ring is reported. Molecular and crystalline structures of most compounds were solved by X-ray diffraction analysis. This made it possible to reveal the influence of the number and arrangement of fluorine atoms in the benzene cycle on the formation of intermolecular hydrogen bonds. It was found that the more fluorine atoms are present in a compound, the higher the dimensionality of the H-bonded structure is. Moreover, the presence of fluorine atoms in the synthesized compounds leads to the emergence of C–F…π interactions affecting crystal packing. The synthesized fluorinated (benzo[d]imidazol-2-yl)methanols may serve as excellent bench compounds for the synthesis of a systematic series of fluorine-containing derivatives to study structure–property correlations in various fields of research from medicine to materials science.

Исследование диэлектрических свойств сополимеров на основе 2,3,4,5,6-пентафторстирола, стирола, 4-фтор-α-метилстирола и α-метилстирола

Three new copolymers based on fluorine-containing derivatives of styrene and α-methylstyrene were obtained. According to the results of the previous stages of the study, copolymers based on styrene derivatives have improved dielectric properties compared to polystyrene and a copolymer of styrene and α-methyl styrene. The dielectric constant ε and dielectric loss tangent tanδ were measured for the initial and synthesized samples of styrene – α-methyl styrene copolymer at Samara Electromechanical Plant OJ-SC (Samara city, Russia). All measurements of dielectric characteristics were carried out at an alternating current frequency of 10 GHz on a pressed copolymer tablet with a diameter of 10 and a thickness of 3 mm. During the experiment, a measuring stand was used, consisting of a high-frequency signal generator G4-83, an electronically counting frequency meter Ch3-54 with a frequency converter YaZCh-43, a measuring amplifier U2-4; low-frequency signal generator G3-109; measuring unit FKDG 418151.002. The results obtained indicate high values of the dielectric constant. For samples of copolymers of α-methylstyrene – 4-fluoro-α-methylstyrene and styrene – 4-fluoro-α-methylstyrene, values of 4.63 and 4.21, respectively, were obtained. These dielectric permittivity values are superior not only to samples previously obtained during the experiment, but also to some other compounds that are widely used in industry. In particular, the dielectric constant of lavsan, which is used in the manufacture of capacitors, is 3.1-3.3. The improved dielectric constant values are probably related to the high-quality composition of the copolymer. Samples of the copolymer containing 4-fluoro-α-methylstyrene are significantly superior to the copolymer with 2,3,4,5,6-pentafluorostyrene for this characteristic. The values of the dielectric loss tangent are in the range from 8.74∙10−4 to 37.4∙10−4. Given the dielectric characteristics of the synthesized copolymers, we can conclude that there are good prospects for the use of fluorine-containing styrene copolymers. The obtained values of permittivity and dielectric loss tangent indicate a good possible competitiveness of new materials based on new copolymers. In the future, it is planned to study a number of other physicochemical properties of these materials in order to obtain the most complete spectrum of their characteristics.

Синтез новых сополимеров на основе 2,3,4,5,6-пентафторстирола, стирола, α-метилстирола и 4-фтор-α-метилстирола

At the first stages of the research work, a copolymer of styrene and α methyl styrene was synthesized by the method of radical emulsion polymerization in an inert atmosphere of argon. The initiator was ammonium persulfate. The molar ratio of the initial monomers of styrene and α-methylstyrene was 70 : 30, respectively. It was found that copolymers synthesized under special controlled conditions have good values of permittivity and dielectric loss tangent. It should be noted that the choice of emulsifier directly affects the values of these indicators. It was previously shown that the most optimal emulsifier is potassium stearate, using which the best values of the dielectric constant and dielectric loss tangent were achieved. At the second stage of the research work, a number of copolymers were synthesized containing 4-methoxystyrene, 4 methyl styrene and α-methyl styrene in their structure. It was experimentally confirmed that the synthesis procedure may be applicable for the preparation of copolymers based on derivatives of styrene and α-methylstyrene. The resulting series of copolymers is highly soluble in methylene chloride; films of each copolymer sample of different thicknesses were obtained by casting from a solution. For this series of copolymer films, the dielectric constant and dielectric loss tangent were determined. It was found that the best values of permittivity and dielectric loss tangent are possessed by a sample of copolymer 4-methoxystyrene and α-methylstyrene. At the latest stage of the study, copolymers of styrene and 2,3,4,5,6-pentafluorostyrene, α-methylstyrene and 4-fluoro-α-methylstyrene, 2,3,4,5,6-pentafluorostyrene and 4-fluoro-α-methylstyrene were synthesized. These fluorine-containing derivatives of styrene and α-methylstyrene easily enough enter into the reaction of radical emulsion copolymerization. The copolymer yields are 53-76%, calculated on the weight of the starting monomers. The structure of a number of newly synthesized copolymers was confirmed by IR spectroscopy. In the future, it is planned to define the values of dielectric constant and dielectric loss tangent for these copolymer samples. It is planned to study the thermomechanical properties of the samples, since fluorine-containing polymers are a promising material for operation at elevated temperatures.

Synthesis, biological evaluation and anti-proliferative mechanism of fluorine-containing proguanil derivatives

Proguanil, a member of biguanide family, has excellent anti-proliferative activities. Fluorine-containing compounds have been demonstrated to have super biological activities including enhanced binding interactions, metabolic stability, and reduced toxicity. In this study, based on the intermediate derivatization methods, we synthesized 13 new fluorine-containing proguanil derivatives, and found that 7a,7d and 8e had much lower IC50 than proguanil in 5 human cancerous cell lines. The results of clonogenic and scratch wound healing assays revealed that the inhibitory effects of derivatives 7a,7d and 8e on proliferation and migration of human cancer cell lines were much better than proguanil as well. Mechanistic study based on representative derivative 7a indicated that this compound up-regulates AMPK signal pathway and downregulates mTOR/4EBP1/p70S6K. In conclusion, these new fluorine-containing derivatives show potential for the development of cancer chemotherapeutic drugs.

Arylation of Adamantanamines: X. Palladium- and Copper-Catalyzed Heteroarylation of Adamantane-Containing Amines with Bromopyridines

The catalytic efficiencies of palladium(0) and copper(I) complexes in the amination of 2-bromopyridine and its fluorine-containing derivatives with (1-adamantyl)methanamine and 2-(1-adamantyloxy)ethanamine were compared. Both types of catalytic systems were shown to be applicable for the preparation of the corresponding N-pyridyl derivatives from 3- and 5-fluoro- and 4-, 5-, and 6-trifluoromethyl-2-bromopyridines. DavePhos was found to be the most efficient ligand in the Pd(0)-catalyzed reactions; however, the reactions with 2-bromo-4-(trifluoromethyl)pyridine and 2-bromo-5-(trifluoromethyl)pyridine were accompanied by formation of a considerable amount of the diarylation product. The diarylation process was significantly suppressed in the presence of copper(I) complexes.

Synthesis and chemical properties of Di(2-fluoro-2-polyfluoroalkyl- alkenyl)sulfides and 2,6-bis(polyfluoroalkyl)-1,4-oxathiine 4,4-dioxides

ABSTRACTDi(1,1-dihydropolyfluoroalkyl)sulfides were synthesized by alkylation of sodium sulfide with tosylates or triflates of the corresponding 1,1-dihydropolyfluoroalkanoles. Dehydrofluorination of the obtained sulfides with strong organic bases such as alkylimino tris(dialkylamino) phosphoranes results in the formation of E-isomers of di(2-fluoro-2-polyfluoroalkyl alkenyl)sulfides. Oxidation of di(1,1-polyfluoroalkyl)sulfides by hydrogen peroxide in acetic acid affords di(1,1-polyfluoroalkyl)sulfones, dehydrofluorination of these compounds under the action of triethylamine allowed access to the E-isomers of di(2-fluoro-2-polyfluoroalkyl-alkenyl)sulfones. The obtained sulfones are convenient starting compounds for the synthesis of previously unknown fluorine-containing derivatives of monocyclic oxathiines.

Synthesis and biological evaluation of new quinoline derivatives as antileishmanial and antitrypanosomal agents

As a part of our project aimed at developing new safe chemotherapeutic agents against tropical diseases, a series of aryl derivatives of 2- and 3-aminoquinoline, some of them new compounds, was designed, synthesized, and evaluated as antiproliferative agents against Trypanosoma cruzi, the parasite responsible for American trypanosomiasis (Chagas’ disease), and Leishmania mexicana, the etiological agent of Leishmaniasis. Some of them showed a remarkable activity as parasite growth inhibitors. Fluorine-containing derivatives 11b and 11c were more than twice more potent than geneticin against intracellular promastigote form of Leishmania mexicana exhibiting both IC50 values of 41.9 μM. The IC50 values corresponding to fluorine and chlorine derivatives 11b–d were in the same order than benznidazole against epimastigote form. These drugs are interesting examples of effective antiparasitic agents with outstanding potential not only as lead drugs but also to be used for further in vivo studies. In addition, the obtained compounds showed no toxicity in Vero cells, which makes them good candidates to control tropical diseases. Regarding the probable mode of action, assayed quinoline derivatives interacted with hemin, inhibiting its degradation and generating oxidative stress that is not counteracted by the antioxidant defense system of the parasite.

Synthesis of Fluorine-Containing Derivatives of 5-Arylisoxazoles and 4,5-Dichlorothiazole

Alkylation of fluorophenols and phenolic aldehydes with 5-phenyl(p-tolyl)-3-chloromethylisoxazole under the Williamson reaction conditions afforded the corresponding ethers. Condensation of the resulting phenolic aldehyde derivatives and 5-phenyl(p-tolyl)isoxazole-3-carbaldehydes with p-fluoroaniline resulted in fluorine-containing azomethines. Acylation of fluorinated amines with 5-(p-tolyl)isoxazole- and 4,5- dichloroisothiazole-3-carbonyl chlorides gave rise to fluorinated amides bearing isoxazole and isothiazole fragments, representatives of which showed a synergistic effect in compositions with insecticides.

Development of a PET radioligand for potassium channels to image CNS demyelination

Central nervous system (CNS) demyelination represents the pathological hallmark of multiple sclerosis (MS) and contributes to other neurological conditions. Quantitative and specific imaging of demyelination would thus provide critical clinical insight. Here, we investigated the possibility of targeting axonal potassium channels to image demyelination by positron emission tomography (PET). These channels, which normally reside beneath the myelin sheath, become exposed upon demyelination and are the target of the MS drug, 4-aminopyridine (4-AP). We demonstrate using autoradiography that 4-AP has higher binding in non-myelinated and demyelinated versus well-myelinated CNS regions, and describe a fluorine-containing derivative, 3-F-4-AP, that has similar pharmacological properties and can be labeled with 18F for PET imaging. Additionally, we demonstrate that [18F]3-F-4-AP can be used to detect demyelination in rodents by PET. Further evaluation in Rhesus macaques shows higher binding in non-myelinated versus myelinated areas and excellent properties for brain imaging. Together, these data indicate that [18F]3-F-4-AP may be a valuable PET tracer for detecting CNS demyelination noninvasively.

Effects of fluorine-containing usnic acid and fungus Beauveria bassiana on the survival and immune-physiological reactions of Colorado potato beetle larvae.

The search for compounds that interact synergistically with entomopathogenic fungi is aimed at enhancing the efficacy and stability of biological products against pest insects, for example, against the Colorado potato beetle (CPB). We hypothesized that fluorine-containing derivatives of usnic acid (FUA) might be candidates for the development of multicomponent bio-insecticides. The aim of this study was to analyze the co-influence of FUA and Beauveria bassiana on the survival and immune-physiological reactions of CPB larvae. Synergy between FUA and B. bassiana was observed after treatment of second, third and fourth larvae instars under laboratory conditions. Furthermore, synergy was observed in field trials in continental climate conditions in southeastern Kazakhstan. In a field experiment, the median lethal time was shortened three-fold, and cumulative mortality for 15 days increased by 36% in the combined treatment compared with a fungal infection alone. FUA treatment delayed larval development, decreased the total hemocyte count, and increased both the phenoloxidase activity in integuments and the detoxification enzyme rate in hemolymph. A combined treatment with fungus and FUA led to increases in the aforementioned changes. Toxicosis caused by FUA provides a stable synergistic effect between FUA and B. bassiana. The combination can be promising for the development of highly efficient products against CPB. © 2017 Society of Chemical Industry.

Intramolecular Hydrogen Bonding Involving Organic Fluorine: NMR Investigations Corroborated by DFT-Based Theoretical Calculations.

The combined utility of many one and two dimensional NMR methodologies and DFT-based theoretical calculations have been exploited to detect the intramolecular hydrogen bond (HB) in number of different organic fluorine-containing derivatives of molecules, viz. benzanilides, hydrazides, imides, benzamides, and diphenyloxamides. The existence of two and three centered hydrogen bonds has been convincingly established in the investigated molecules. The NMR spectral parameters, viz., coupling mediated through hydrogen bond, one-bond NH scalar couplings, physical parameter dependent variation of chemical shifts of NH protons have paved the way for understanding the presence of hydrogen bond involving organic fluorine in all the investigated molecules. The experimental NMR findings are further corroborated by DFT-based theoretical calculations including NCI, QTAIM, MD simulations and NBO analysis. The monitoring of H/D exchange with NMR spectroscopy established the effect of intramolecular HB and the influence of electronegativity of various substituents on the chemical kinetics in the number of organic building blocks. The utility of DQ-SQ technique in determining the information about HB in various fluorine substituted molecules has been convincingly established.