Search

Heteroanalogs of ascidian alkaloids have been synthesized, and for the first time 10 different types of saturated carbo- and heteroannulated pyridones have been obtained. A new method for the formation of decahydro[1,3]oxazolo[2,3-j]quinoline and octahydro-5H-cyclopenta[b][1,3]oxazolo[3,2-a]pyridine was proposed. The synthesis of these heterocycles is based on the three-component cyclization of trifluoroacetoacetic ester and cycloketones with 1,2- and 1,3-dinucleophiles. It was found that reactions with amino alcohols are distinguished by the possibility of isolating carbocyclopyridones of various degrees of saturation. The diastereomeric structure of the synthesized heterocycles has been studied, and the mechanism of their formation has been proposed. Antitumor, anti-influenza and analgesic agents have been found among the synthesized compounds.

New conjugates of tacrine and salicylamide with alkylene spacers were synthesized and evaluated as potential multifunctional agents for Alzheimer's disease (AD). The compounds exhibited high acetylcholinesterase (AChE, IC

The paper presents the results of a comparative analysis of the component composition of alcoholic extracts of particles of Calendula officinalis L. decorative Neon mark: stalks, roots, leaves, flowers, etc., by gas chromatography/mass spectrometry. As a result of the study, more than 30 biologically active compounds (BAС) were identified that belong to different classes of organic compounds (including sesquiterpens, hydrocarbons, fatty acids and their ethyl esters, phytosterols). Their relative quantitative assessment was calculated by the method of internal normalization. It was found that the mass yield of extractable substances depends on the part of the plant used: the maximum (about 10%) from the petals and flowers, the minimum (less than 1%) from the roots. It has been established that the detected BAC is contained in all parts of the plant, but their content varies greatly: the most enriched are petals and flowers, the least - the stems, leaves, roots. Vitamin E is found only in flowers, flower petals and calyxes. The presence of a large number of phytosteros in Calendula officinalis L. is of interest for further pharmacognostic studies of this plant.

New pyrazolo[1,5-a]pyrimidinones functionalized with the tolylhydrazone fragment were obtained as a result of cyclization of 3-oxo-2-(tolylhydrazinylidene) esters with 3-aminopyrazoles. In this case, methyl- and trifluoromethyl-containing derivatives regioselectively form pyrazolo[1,5-a]pyrimidin-7-ones, while cyclization of polyfluoroalkyl-substituted analogs can take place competitively with the formation of dihydropyrazolo[1,5-a]pyrimidin-5-ones, for which ring-chain isomerism is characteristic in solution. It was found that 6-(tolylhydrazinylidene)pyrazolo[1,5-a]pyrimidin-7-ones have a pronounced analgesic activity. The trifluoromethyl-containing analog selectively inhibits carboxylesterase in micromolar concentration.

A series of new 5-aryl-2,2'-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)

In the direct C–H arylation with arylhalogenides in the presence of Pd(OAc)2, trifluoromethyl-containing antipyrine reacts very slowly and incompletely owing to the low nucleophilicity of its C4 center. However, it was effective in modifying polyfluoroalkyl-substituted 4-bromo- and 4-iodo antipyrines by the Suzuki and Sonogashira reactions. It was established that using Pd2(dba)3 as catalyst and XPhos as phosphine ligand was the optimal catalytic system for the synthesis of 4-aryl- and 4-phenylethynyl-3-polyfluoroalkyl-antipyrines. Moreover, iodo-derivatives as the initial reagents were found to be more advantageous compared to bromo-containing analogs. It was found that 4-phenylethynyl-5-CF3-antipyrine has a moderate activity against the influenza virus A/Puerto Rico/8/34 (H1N1) and 4-iodo-5-CF3-antipyrine reveals a weak activity against the vaccine virus (strain Copenhagen) and bovine diarrhea virus (strain VC-1).

Fluorine-containing analogues of non-steroidal antiinflammatory drugs Tribuzone and Ketazone have been synthesized by reaction of 1,2-diphenylpyrazolidine-3,5-dione with polyfluoroalkyl-containing 3- and 2-oxo esters. Ethyl 3-(pyrazolidin-4-yl)-3-(polyfluoroalkyl)prop-2-enoates have been obtained as Knoevenagel reaction products from 3-oxo esters in the presence of l-proline. Unlike with 3-oxo esters, addition of ethyl 3,3,3-trifluoro-2-oxopropanoate under basic conditions afforded ethyl 2-(pyrazolidin-4-yl)-3,3,3-trifluoro-2-hydroxypropanoate or its salt without elimination of a water molecule.

Polyfluorinated analogues of salicylamide and p-aminosalicylic acid have been synthesized based on methyl polyfluorosalicylates. Polyfluorosalicylamides were obtained by the reaction with aqueous ammonia, while 4-aminopolyfluorosalicylic acids were prepared in two steps via regio-oriented nucleophilic replacement of para-positioned fluorine atom with azido group followed by its reduction. 3,4,5-Trifluorosalicylamide showed pronounced analgesic in vivo activity in hot plate test while 4-amino-3,5-difluorosalicylic acid revealed high tuberculostatic activity.

Background Formally belonging to the non-steroidal anti-inflammatory drug class pyrazolones have long been used in medical practices. Objective Our goal is to synthesize N-methylated 1-aryl-3-polyfluoroalkylpyrazolones as fluorinated analogs of antipyrine, their isomeric O-methylated derivatives resembling celecoxib structure and evaluate biological activities of obtained compounds. Methods In vitro (permeability) and in vivo (anti-inflammatory and analgesic activities, acute toxicity, hyperalgesia, antipyretic activity, "open field" test) experiments. To suggest the mechanism of biological activity, molecular docking of the synthesized compounds was carried out into the tyrosine site of COX-1/2. Results We developed the convenient methods for regioselective methylation of 1-aryl-3- polyfluoroalkylpyrazol-5-ols leading to the synthesis N-methylpyrazolones and O-methylpyrazoles as antipyrine and celecoxib analogs respectively. For the first time, the biological properties of new derivatives were investigated in vitro and in vivo. Conclusion The trifluoromethyl antipyrine represents a valuable starting point in design of the lead series for discovery new antipyretic analgesics with anti-inflammatory properties.

Five- and six-membered fluorine-containing azaheterocycles were synthesized based on available furan-3(2H)-ones, and the influence of the nature of the fluoroalkyl substituent on the direction of the chemical transformations by the action of N,N- and N,O-binucleophiles was revealed.

Currently, the chemistry of organofluorine compounds is a leading and rapidly developing area of organic chemistry. Fluorine present in a molecule largely determines its specific chemical and biological properties. This thematic issue covers the trends of organofluorine chemistry that have been actively developed in Russia the last 15 – 20 years. The review describes nucleophilic substitution and heterocyclization reactions involving fluorinated arenes and quinones and skeletal cationoid rearrangements in the polyfluoroarene series. The transformations involving CF3-substituted carbocations and radical cations are considered. Heterocyclization and oxidative addition reactions of trifluoroacetamide derivatives and transformations of the organic moiety in polyfluorinated organoboranes and borates with retention of the carbon – boron bond are discussed. Particular attention is devoted to catalytic olefination using freons as an efficient synthetic route to fluorinated compounds. The application of unsymmetrical fluorine-containing N-heterocyclic carbene ligands as catalysts for olefin metathesis is demonstrated. A variety of classes of organofluorine compounds are considered, in particular, polyfluorinated arenes and 1,2-diaminobenzenes, 1-halo-2-trifluoroacetylacetylenes, α-fluoronitro compounds, fluorinated heterocycles, 2-hydrazinylidene-1,3-dicarbonyl derivatives, imines and silanes. The potential practical applications of organofluorine compounds in fundamental organic chemistry, materials science and biomedicine are outlined. The bibliography includes 1019 references.

We propose different methods for the synthesis of 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones. The simplest and most convenient procedure relies on sequential one-pot treatment of polyfluoroalkyl-3-oxoesters with hydrazine and sodium nitrite in acetic acid. It was established that 4-hydroxyimino-5-polyfluoroalkylpyrazol-3-ones exist in solid state and in solutions as mixtures of Z,Е-isomers of the hydroxyimine tautomer. The synthesized compounds were characterized with respect to in vivo analgesic activity and acute toxicity.

The synthesis of novel dinuclear lanthanide complexes with formulas [(LnL3)(LiL)(MeOH)] (1–3) and [(LnL3)(LiL)(H2O)] (4–6) (Ln = Eu(III), Tb(III), Dy(III)) based on functionalized lithium β-diketonate (LiL) is reported. The coordination environment of the Ln(III) ion is formed by oxygen atoms of both the 1,3-dicarbonyl moiety and the acetal group. Depending on the solvent used for the crystallization, methanol or water molecules participate in the coordination with Li(I) ions affecting the crystal structure of complexes. In contrast to [(LnL3)(LiL)(H2O)] 4–6, a series of complexes [(LnL3)(LiL)(MeOH)] 1–3 showed mechanoluminescence properties, thereby demonstrating the relationship between the observed optical properties and crystal packing architecture. The magnetic measurements of [(LnL3)(LiL)(MeOH)] 1–3 revealed SMM behavior of [(DyL3)(LiL)(MeOH)] 3 at low temperatures (Ueff is 37.7 cm−1).

4-Nitroso-3-trifluoromethyl-5-alkyl[(het)aryl]pyrazoles were synthesized via one-pot nitrosation of 1,3-diketones or their lithium salts followed by treatment of hydrazines. Reduction of nitroso-derivatives made it possible to obtain 4-amino-3-trifluoromethylpyrazoles chlorides. According to computer-aided calculations, all synthesized compounds are expected to have acceptable ADME profile for drug design. Tuberculostatic, antibacterial, antimycotic, antioxidant and cytotoxic activities of the compounds were evaluated in vitro, while their analgesic and anti-inflammatory action was tested in vivo along with acute toxicity studies. N-Unsubstituted 4-nitrosopyrazoles were the most effective tuberculostatics (MIC to 0.36 μg/ml) and antibacterial agents against Streptococcus pyogenes (MIC to 7.8 μg/ml), Staphylococcus aureus, S. aureus MRSA and Neisseria gonorrhoeae (MIC to 15.6 μg/ml). 4-Nitroso-1-methyl-5-phenylpyrazole had the pronounced antimycotic action against a wide range of fungi (Trichophyton rubrum, T. tonsurans, T. violaceum, T. interdigitale, Epidermophyton floccosum, Microsporum canis with MIC 0.38–12.5 μg/ml). N-Unsubstituted 4-aminopyrazoles shown high radical-scavenging activity in ABTS test, ORAC/AAPH and oxidative erythrocyte hemolysis assays. 1-Methyl-5-phenyl-3-trifluoromethylpyrazol-4-aminium chloride revealed potential anticancer activity against HeLa cells (SI > 1351). The pronounced analgesic activity was found for 4-nitroso- and 4-aminopyrazoles having phenyl fragment at the position 5 in “hot plate” test. The most of the obtained pyrazoles had a moderate acute toxicity.

The synthesis of bis(salicylato)Cu(II) and Co(II) chelates based on methyl trifluorosalicylate and the corresponding M(OAc) 2 in the presence of alkali is reported. The following reaction with 2,2’-bipyridine and 1,10 phenanthroline in refluxing methanol affords heteroligand complexes containing methyl trifluorosalicylate and azaheterocyclic ligands in the ratio 2:1. However, the refluxing of Co(II) chelates in ethanol resulted in transesterification of methyl ester group to form heteroligand complexes of ethyl trifluorosalicylate while Cu(II) chelates underwent hydrolysis of ester group to obtain heteroligand complexes of trifluorosalicylic acid. The structures of obtained metal complexes were confirmed by X-Ray diffraction experiment, IR spectroscopy and elemental analysis. The antimycotic and antibacterial activities of synthesized metal complexes were investigated. The heteroligand metal complexes were found to exhibit moderate anti-Candida albicans activity. Among new series of complexes, the most activity showed the mixed metal complexes of trifluorosalicylates and 1,10-phenanthroline revealing a wide range of action in relation to pathogenic fungi and bacteria.

Ethyl 2-(ethoxymethylene)-4,4,4-trifluoroacetoacetate reacts with cesium fluoride under mild conditions to give triethyl 1,3,5-benzenetricarboxylate. The plausible mechanism of this transformation includes step-by-step reactions of detrifluoroacetylation, addition-elimination and cyclization of three molecules of the starting CF3-alkoxyenone.

Aim and Objective: The objective of our work was to study the peculiarities of transformations of fluorine-containing flavone-3-carboxylates with N-nucleophiles, including biogenic amines and amino acids. Materials and Methods: 6,7,8-Trifluoro and 5,6,7,8-tetrafluoroflavone-3-carboxylates were involved in interactions with a number of N-nucleophiles, such as pyrrolidine, morpholine, proline, arginine, gammaaminobutyric acid, beta-alanine, histamine, dopamine and amantadine under different reaction conditions. All synthesized compounds were characterized by NMR 1H, 19F, (NMR 13C for some compounds) and IR spectroscopic data, and elemental analysis. Results: 3-(Ethoxycarbonyl)polyfluoroflavones react with morpholine, pyrrolidine and L-proline to form 7- monosubstituted flavone-3-carboxylates. For the reactions of tetrafluoroflavone with pyrrolidine and morpholine, the formation of 5,7-disubstituted products is also possible. Interaction with gamma-aminobutyric acid leads to the 4-{[3-ethoxy-2-(2-hydroxypolyfluorobenzoyl)-3-oxo-1-phenylprop-1-enyl]amino}butanoic acids as a result of the pyrone ring opening. In reactions with dopamine, histamine, L-arginine and β-alanine, polyfluoroflavone-3-carboxylates underwent a chromone-coumarin rearrangement. 3-(Ethoxycarbonyl)tetrafluoroflavone forms with amantadine the nucleophilic aromatic substitution product, while trifluoro-substituted analog gives the chromone-coumarin rearrangement product. Conclusion: This work showed possibilities of chemical modification of polyfluorinated flavones in the reactions with amines depending on the structure of the nucleophilic reagent. Synthesized compounds are of interest for biological testing.

The condensation of 5-(1-hydrazinylideneethyl)-3-(trifluoromethyl)-1H-pyrazole with trimethyl orthoacetate, dimethylformamide dimethyl acetal, and aryl thioisocyanates resulted in a series of functionalized pyrazoles and their tuberculostatic activity was studied.

An efficient three-step method for the synthesis of new polyfluoroflavones has been proposed using substituted benzoyl chlorides and 2-hydroxyacetophenone to form the initial 2-(polyfluoroaroyloxy)acetophenones, which are transformed into 1,3-diaryl-1,3-diketones as a result of the Baker-Venkataraman rearrangement. The ability of these 1,3-diketones to undergo keto-enol and ring-chain tautomerism was found, depending on the nature of the solvent. Under acid- or base-catalyzed conditions the alternative cyclization routes of fluorine-containing 1,3-diaryl-1,3-diketones into A- and B-ring halogenated flavones have been reported. The anti-influenza and fungistatic effects of the synthesized compounds were evaluated, and products with promising antimicrobial properties were found.

An expanded series of alkyl 2-arylhydrazinylidene-3-oxo-3-polyfluoroalkylpropionates (HOPs) 3 was obtained via Cu(OAc)2-catalyzed azo coupling. All were nanomolar inhibitors of carboxylesterase (CES), while moderate or weak inhibitors of acetylcholinesterase and butyrylcholinesterase. Steady-state kinetics studies showed that HOPs 3 are mixed type inhibitors of the three esterases. Molecular docking studies demonstrated that two functional groups in the structure of HOPs, trifluoromethyl ketone (TFK) and ester groups, bind to the CES active site suggesting subsequent reactions: formation of a tetrahedral adduct, and a slow hydrolysis reaction. The results of molecular modeling allowed us to explain some structure-activity relationships of CES inhibition by HOPs 3: their selectivity toward CES in comparison with cholinesterases and the high selectivity of pentafluoroethyl-substituted HOP 3p to hCES1 compared to hCES2. All compounds were predicted to have good intestinal absorption and blood-brain barrier permeability, low cardiac toxicity, good lipophilicity and aqueous solubility, and reasonable overall drug-likeness. HOPs with a TFK group and electron-donor substituents in the arylhydrazone moiety were potent antioxidants. All compounds possessed low cytotoxicity and low acute toxicity. Overall, a new promising type of bifunctional CES inhibitors has been found that are able to interact with the active site of the enzyme with the participation of two functional groups. The results indicate that HOPs have the potential to be good candidates as human CES inhibitors for biomedicinal applications.

To search for effective and selective inhibitors of carboxylesterase (CaE), a series of 7-hydroxy-7-polyfluoroalkyl-4,7-dihydroazolo[5,1-c][1,2,4]triazines has been synthesized. Their inhibitory activity against acetylcholinesterase, butyrylcholinesterase, and CaE were investigated using the methods of enzyme kinetics and molecular docking. It was shown that the tested compounds are reversible selective CaE inhibitors of mixed type. Elongation of the polyfluoroalkyl substituent and the presence of an ester, preferably the ethoxycarbonyl group, enhance inhibitory activity toward CaE. Furthermore, the compounds with a tetrazole ring are more active against CaE than their triazole analogues. The obtained kinetic data are well explained by the results of molecular docking, according to which there is a similar orientation of triazolo- and tetrazolotriazines in the active site of CaE and the opposite one for pyrazolotriazines. In the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) assay, all of the studied tetrazolotriazines and some pyrazolotriazines demonstrated good antiradical activity comparable with a standard antioxidant, Trolox. The leading compounds were nonafluorobutyl substituted tetrazolo- and 7-phenylpyrazolotriazines, which possess effective and selective CaE inhibitory activity as well as additional useful radical-scavenging properties.

The synthesis of 1-aminoethyl-6-alkyl-4-polyfluoroalkylpyridin-2-ones based on acid cleavage of 7-hydroxy-7-polyfluoroalkylhexahydroimidazo[1,2-a]pyridin-5-ones is reported. Depending on the reaction conditions pyridones can be obtained as bases, salts, acetylamines or products of their intramolecular cyclization - dihydroimidazopyridines. The high tuberculostatic activity was revealed for synthesized compounds.

The reactivity of polyfluoroalkyl-containing pyrazoles has been estimated using the quantum chemical calculations. A good regioselectivity in the methylation of polyfluoroalkylpyrazoles was reached while varying the reaction conditions. Under basic conditions, methylation of such pyrazoles led to the preferred formation of 3-R F -pyrazoles, whereas the use of dimethyl sulfate in the absence of a base resulted in the predominant formation of 5-R F -pyrazoles. A proposed mechanism of methylation was discussed.

The one-step preparation of diethyl 2-ethoxy-6-CF3-2H-pyran-3,5-dicarboxylate via the condensation of ethyl 4,4,4-trifluoroacetoacetate with CH(OEt)3 has been reported and a plausible mechanism for this transformation is discussed. To demonstrate the synthetic potential of the obtained pyran, the reactions with ammonia and aromatic amines to give trifluoromethylated pyridine derivatives are presented.

A novel N,N ’ ,N ” ,O-tetradentate Schiff base ligand was obtained by the condensation of salicylaldehyde and 5-(1-hydrazono-ethyl)-3-(trifluoromethyl)pyrazole. Five-coordinated dinuclear copper(ii) complex with this ligand was characterized by XRD analysis, magnetometry and voltammetry.

Regiospecific ribosylation of 3-polyfluoroalkyl-5-phenylpyrazoles with 1,2,3,5-tetra-O-acetyl-β-d-ribofuranose in the presence of tin(iv) chloride followed by deacetylation affords 1-(β-d-ribofuranosyl)-3-polyfluoroalkyl-5-phenyl- 1H-pyrazoles. These derivatives as well as starting pyrazoles were tested for anti-influenza activity.