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Background: Hepatoprotectors, currently used in clinical practice, often show low efficacy. One of the promising goals in the therapy of liver diseases is the targeted synthesis of smallmolecule drugs with hepatoprotective activity. Some heterocycles, such as 1,4-dihydropyridines, are proven to be good hepatoprotectors. Objective: This study aimed to prepare and investigate the hepatoprotective effects of some dihydro- and tetrahydro pyridines using the experimental rat model of tetrachloromethane (CCl4)- induced acute liver damage. Methods: Several 1,4-dihydropyridines and 1,2,3,4-tetrahydropyridines were synthesized by the reaction of cyanothioacetamide with carbonyl compounds and active methylene compounds, such as Meldrum’s acid, ethyl cyanoacetate or β-keto esters, followed by S-alkylation of intermediate pyridine-2-thiolates. In silico prediction studies were performed to explore the possible protein targets. Using virtual bioscreening tools, we selected the six most promising compounds from the library of new partially saturated pyridines. Six novel compounds were characterized by IR, 1H, 13C DEPTQ NMR spectroscopy, 2D NMR experiments (1H–13C HSQC, 1H–13C HMBC), HRMS (ESI), and elemental analysis. The hepatoprotective effects were studied in vivo on eighty white rats with CCl4-induced liver damage. Biochemical studies, including thymol turbidity test and measurements of levels of bilirubin, alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in the blood of rats, were performed. Results: Five of six studied compounds showed a good hepatoprotective effect on a rat model of tetrachloromethane (CCl4)-induced acute hepatitis. The blood of rats in the experimental groups revealed significantly lower levels of total bilirubin, alanine aminotransferases, aspartate aminotransferases, thymol turbidity and alkaline phosphatase compared to the control group of rats with acute toxic tetrachloromethane hepatitis. Conclusion: Our results suggests that compound, (benzyl 4-(4-chlorophenyl)-5-cyano-6-({2-[(3,4- dimethylphenyl)amino]-2-oxoethyl}thio)-2-methyl-1,4-dihydropyridine-3-carboxylate), can be considered as candidate for further preclinical studies. Moreover, as per our knowledge, this is the first report on the hepatoprotective effects of the 1,2,3,4-tetrahydropyridine series.

trans-2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH2 under noncatalyzed Mannich conditions.

A series of new hybrid molecules containing 2-furyl and partially saturated pyridine fragments was obtained based on the reaction of cyanothioacetamide with furfural and 1,3-dicarbonyl compounds. The resulting compounds were tested in vivo for analgesic activity (rats) in the orofacial trigeminal pain test. Some the tested compounds showed an antinociceptive effect, superior to that of the reference drug (metamizole sodium).

Abstract The reaction of 2-thioxoazines with chlorokojic acid in the presence of KOH in DMF led to the formation of new hybrid molecules containing fragments of kojic acid and azaheterocycle linked by the SCH2 spacer. In silico prediction of bioavailability parameters was carried out, possible protein targets were predicted by the protein ligand docking method.

Condensation of benzaldehyde with malononitrile and malononitrile dimer (2-aminopropene-1,1,3-tricarbonitrile) in the presence of an excess of morpholine in ethanol afforded the morpholinium salt of 6-amino-2-(dicyanomethylene)-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile. The latter, under the Mannich reaction conditions with the participation of primary amines and formaldehyde, gives 6-amino-2-(dicyanomethylene)-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile, 2-(dicyanomethylene)-6-(hydroxymethylamino)-4-phenyl-1,2-dihydropyridine-3,5-dicarbonitrile or zwitterionic aminomethylation products, 6-(ammoniomethylamino)-3,5-dicyano-4-phenylpyridin-2-yl)dicyanomethanides. Structure of the obtained compounds was established using 2D NMR spectroscopy and single crystal X-ray diffraction analysis. In silico predictive analysis of the biological activity of new compounds was carried out.

The reaction of 2,6-dichloro-4-methylnicotinonitrile with malononitrile dimer in the presence of triethylamine leads to regioselective nucleophilic substitution of the chlorine atom at position 6 with the formation of triethylammonium 2-amino-3-(6-chloro-5-cyano-4-methyl-pyridin-2-yl)-1,1,3-tricyanoprop-2-en-1-ide. The structure of the product was confirmed by spectral methods and X-ray diffraction analysis.

The reaction of partially saturated derivatives of 3-aminothieno[2,3-b]pyridine-2-carboxamide with phthalic anhydride in acetic acid or DMF on heating leads to the formation of thieno[2′,3′:5.6]pyrimido[2,1-a]isoindole derivatives fused with a pyridine or quinoline core. One of the obtained compounds shows a pronounced UV fluorescence.

Unusual cascade transformation was developed involving microwave assisted electrocyclic cyclization of aci (alkylideneazinic acid) forms of nitrovinylindoles acting as heterotrienes. Subsequent one-pot reduction allowed for efficient access to β-carbolines, including several natural products, alkaloids norharmane, harmane and eudistomin N.

A number of europium(III), terbium(III), and gadolinium(III) coordination compounds with N-substituted phthalamic acids were synthesized. Composition and structure of the ligands and the obtained complex compounds were confirmed by NMR and IR spectroscopy and thermogravimetric analysis. It was found that terbium(III) and europium(III) coordination compounds with N-phenylphthalamic acid possess the most pronounced luminescence.

Abstract The reaction of 2-amino-1,1,3-tricyanopropene (malononitrile dimer) with isothiocyanates leads to 1-substituted 4,6-diamino-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitriles or 4,6-diamino-2-(phenylimino)-2H-thiopyran-3,5-dicarbonitrile, depending on the conditions. Quantum-chemical modeling of the IR spectra and reaction routes for the synthesized compounds was carried out. In silico predictive analysis of potential protein targets, compliance with bioavailability criteria, and ADMET parameters was performed.

Sequential reaction of cyclohexanone with malononitrile and 2-aminopropene-1,1,3-tricarbonitrile in the presence of potassium hydroxide or sodium ethylate in ethanol gave 4-imino-2-(dicyanomethylene)-3-azaspiro[5.5]undecane-1,5-dicarbonitrile. The latter reacted with primary amines and an excess of formaldehyde to form new 2-(dicyanomethylene)-3,7-diazaspiro[bicyclo[3.3.1]non-3-ene-9,1′-cyclohexane]-1.5-dicarbonitrile derivatives. Contrary to the literature data, the reaction of cyclohexanone with 2-aminopropene-1,1,3-tricarbonitrile in benzene in the presence of piperidine and glacial acetic acid led to the formation of 2,4-diamino-5,6,7,8-tetrahydronaphthalene-1,3-dicarbonitrile.

The reaction of aromatic aldehydes with malononitrile, ethyl or butyl cyanoacetate and acetylacetone in the presence of NaOH under mild conditions (EtOH, 25°C) led to the formation of new series of (1S,5R,6R,9R)/(1R,5S,6S,9S)-2-amino-6,9-diaryl-7-acetyl-8-methyl-4-oxo-5-cyano-3-azabicyclo[3.3.1]nona-2,7-diene-1-carboxylic acids esters. A plausible mechanism of the cascade reaction was proposed.

New Eu3+ and Tb3+ complex compounds [Ln(H2O)2L2]Cl∙H2O were synthesized on the basis of coumarin-3-carboxylic acid and its derivatives. Composition and structure of the ligands and the complex compounds were confirmed by NMR and IR spectroscopy, thermogravimetry, and complexometric titration. Europium(III) coordination compounds with coumarin-3-carboxylic and 6-nitrocoumarin-3-carboxylic acids show effective luminescence.

The reaction of (2E,4E)-5-phenyl-2-cyano-2,4-pentadienethioamide or (E)-3-(2-nitrophenyl)acrolein and cyanothioacetamide with α-bromoketones afforded new (2E,4E)-5-aryl-2-(4-arylthiazol-2-yl)penta-2,4-dienenitriles. Direct bromination of the latter by the action of bromine in DMF proceeded regiospecifically at the C5 position of the thiazole ring without affecting the diene system and leads to the formation of new series of (2E,4E)-5-aryl-2-(5-bromo-4-arylthiazol-2-yl)penta-2,4-dienenitriles.

Bromination of (2E)-3-aryl(hetaryl)-2-[4-aryl(hetaryl)-1,3-thiazol-2-yl]acrylonitriles proceeds regioselectively at the C5 atom of the thiazole ring with the formation of new (2E)-3-aryl(hetaryl)-2-[5-bromo-4-aryl(hetaryl)-1,3-thiazol-2-yl]acrylonitriles. The latter were alternatively obtained by the reaction of aldehydes, cyanothioacetamide, α-bromoketones and bromine in the presence of triethylamine in DMF. Structure of the key compounds was confirmed using 2D NMR spectroscopy and single crystal X-ray diffraction analysis.

The reaction of cyanothioacetamide with aromatic aldehydes and 1,3-dicarbonyl compounds followed by aminomethylation or S-alkylation gave a series of heterocyclic derivatives with a 1,2,3,4-tetrahydropyridine or 1,4,5,6,7,8-hexahydroquinoline fragment. The resulting compounds were tested for analgesic activity in vivo. Some of the prepared compounds showed an antinociceptive effect superior to that of ketorolac in dynamics.

1,6-Diamino-2-oxo-1,2,3,4-tetrahydropyridine-3,5-dicarbonitriles under the action of primary aliphatic amines and an excess of 37% formalin in ethanol were converted into 2,3,8,9-tetrahydro-6,10-methano[1,2,4]triazolo[1,5-a][1,5]diazocine-6,10(7H)-dicarbonitrile derivatives. At the same time, the Mannich reaction in the case of 1,6-diamino-4-aryl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles proceeds ambiguously, and, depending on the conditions, gives either N-ethoxymethylation products or 1,2,4-triazolo[1,5-a]pyridine derivatives. In silico predictive analysis of the biological activity of new compounds was carried out.

The sequential reaction of furfural with cyclic secondary amines and further with benzaldehyde and cyanoacetates affords new 2,4-dicyano-8-(R2N)-6-oxo-3-phenylbicyclo[3.2.1]-octane-2,4-dicarboxylates as rac-(1R,2R,3R,4S,5S,8R)-diastereomers. The structures of the reaction products were determined by X-ray diffraction.

The reaction of N-substituted amides of 3-amino-4,6-diarylthieno[2,3-b]pyridine-2-carboxylic acids with ninhydrin in the presence of catalytic amounts of sulfuric acid gave 1′-spiro[indene-2,2′-pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine]-1,3,4′(3′H)-triones. Structure of a number of key compounds was studied using 2D NMR spectroscopy; the bioavailability parameters of the obtained compounds in silico were calculated. In a laboratory experiment, a moderate antidote effect was revealed with respect to the 2,4-D herbicide for one compound.

New complex compounds LnL3·nH2O (n = 5–10) have been synthesized on the basis of Eu3+, Gd3+, and Tb3+ salts and quinoline-4-carboxylic acid derivatives obtained via the Pfitzinger reaction. Composition and structure of the ligands and the resulting complex compounds have been confirmed by NMR and IR spectroscopy, thermogravimetry, and complexometric titration. Europium complex with 1,2,3,4-tetrahydroacridine-9-carboxylic acid has exhibited efficient luminescence.

The reaction of 3-pentylpentane-2,4-dione with cyanothioacetamide afforded 4,6-dimethyl-5-pentyl-2-thioxo-1,2-dihydropyridine-3-carbonitrile. Alkylation of the latter led to the formation of 2-alkylsulfanyl-4,6-dimethyl-5-pentylpyridine-3-carbonitriles or 3-amino-4,6-dimethyl-5-pentylthieno[2,3-b]pyridines, depending on the alkylating agent and reaction conditions. The structures of the key compounds were proved by 2D NMR spectroscopy and X-ray analysis. Biological activity of the synthesized compounds was evaluated in silico. Some compounds were experimentally found to stimulate growth of sunflower seedlings.

A novel one-pot method based on the sequence of the Fisher reaction between nitroacetophenone and phenylhydrazines, the reduction with metallic tin directly in polyphosphoric acid, and acylation has been developed for the synthesis of indoloquinolines. The obtained indolo-[3,2-c]quinolines are precursors of the analogs of isocryptolepine alkaloid.

The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-5-hydroxy-5- methyl-2,4-di(ethoxycarbonyl)cyclohexanones in acetic acid furnished previously unknown 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazoline derivatives.

2,4-Dioxo-3-azaspiro[5.5]undecane-1,5-dicarbonitrile reacted with primary amines and formaldehyde on heating in boiling ethanol to give mixtures of 7-alkyl-2,4-dioxo-3,7-diazaspiro[bicyclo[3.3.1]nonane- 9,1′-cyclohexane]-1,5-dicarbonitriles and their ammonium salts. The former were isolated in 26–71% after acidification of the reaction mixture.

Aminomethylation of xanthane hydride (5-amino-1,2,4-dithiazole-3-thione) with the RNH2–HCHO system has resulted in the formation of the derivatives of new heterocyclic system (3,7-dihydro-5H-[1,2,4]-dithiazolo[4,3-a][1,3,5]triazine) in low yields. The reaction of xanthane hydride with dicyandiamide has led to thioammeline [4,6-diamino-1,3,5-triazine-2(5Н)-thione]. Some practically important properties of xanthane hydride and its derivatives have been investigated. Xanthane hydride has efficiently exhibited carbon steel corrosion in neutral aqueous media. The prepared compounds have not exhibited growth-regulating or antidote activity to herbicide 2,4-D.

Upon treatment with chloroacetyl chloride, 3-aminothieno[2,3-b]pyridines gave the corresponding chloroacetamides. The latter readily react with sodium thiosulphate to afford water soluble S-alkylthiosulphates with pharmacophoric heterocyclic units.

S-alkyl derivatives of thiobarbituric acid easily react with arylmethylene malononitriles in the presence of base to give new 7-amino-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carbonitriles. The structure of products and the mechanism of formation are discussed.

2,2-Dimethyl-5-((phenylamino)methylene)-1,3-dioxane-4,6-dione, prepared by the reaction of Meldrum’s acid with triethyl orthoformate and aniline, reacts with active methylene nitriles to afford 2-oxo-1,2-dihydropyridine-3-carboxylic acid derivatives, which are useful as drug precursors or perspective ligands.

(3-Cyano-5,6,7,8-tetrahydroquinolin-2(1H)-ylidene)malononitriles were prepared for the first time by the reaction of arylmethylidene malononitrile dimers with N-(1-cyclohexen-1-yl) morpholine.

The aminomethylation of 4,4-dialkyl-2,6-dioxopiperidine-3,5-dicarbonitriles (Guareschi imides) was studied for the first time. When the Guareschi imides were treated with primary aliphatic amines and an excess of formaldehyde, 2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitriles were obtained in varying yields (15–67%). The structure of 9,9-dimethyl-7-(2-methylpropyl)-2,4-dioxo-3,7-diazabicyclo[3.3.1]nonane-1,5-dicarbonitrile was studied by X-ray diffraction analysis.

The review describes the history of development of organic chemistry in higher schools of Russia over a period of 170 years, since the emergence of organic chemistry in our country till now.

The aminomethylation reaction of 9-benzyl-2,4-dioxo-3,9-diazaspiro[5.5]undecane-1,5-dicarbonitrile hydrochloride in the presence of primary aliphatic amines and an excess of 37% aqueous formaldehyde led to the formation of 7-substituted 1'-benzyl-2,4-dioxo-1H,5Hspiro[3,7-diazabicyclo[3.3.1]nonane-9,4'-piperidine]-1,5-dicarbonitrile derivatives.

The reaction of tetra(phenylethynyl)tin with aromatic aldehydes in the presence of ZnCl2 afforded α-acetylene ketones in a yield of 77–98%.

A highly efficient synthetic route to 6,7-dihydro-1H-cyclopenta[gh]perimidines has been proposed on the basis of a novel reaction of nitroalkanes with 4,5-diaminoacenaphthene in the presence of polyphosphoric acid. The reaction involves phosphorylation of the aci-nitro compound, followed by intramolecular cyclization.

A highly efficient protocol for acid-mediated peri-annulation of perimidines with pyrimidines was developed. Pyrimidines, used as surrogates for 1,3-dicarbonyl compounds allow for furnishing benzo[gh]perimidines, including hardly available analogs, non-substituted, or mono-substituted at C-6, C-8. Limitations of reactions employing 5-bromopyrimidines are investigated.

The reaction of tetraalkynyltin with aldehydes was studied for the first time. The reaction was shown to proceed as a tandem process of nucleophilic addition of tin acetylide to aldehyde followed by Oppenauer-type oxidation of produced tin alcoholates, and may be used as a convenient one-pot approach to acetylenic ketones. The advantages and limitations of the proposed method are discussed.

A novel highly efficient preparative method for the synthesis of substituted indoles using conjugate addition of nucleophiles to 3-(2-nitrovinyl)indoles has been developed. The addition of nucleophiles generated in the presence of a base from CH acids was investigated. The studied reactions proceed quickly and smoothly under the conditions of microwave activation and do not require protection of the indole nitrogen atom.

The reaction of furfural with secondary amines and isopropyl cyanoacetate leads to the formation of the previously unknown diisopropyl 8-(dialkylamino)-2,4-dicyano-3-(2-furyl)-6-oxobicyclo[3.2.1]octane-2,4-dicarboxylates. The tructure of the products was confirmed by NMR and X-ray analysis.

The reaction of 5-amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile with 3-aryl-2,4-di (ethoxycarbonyl)-5-hydroxy-5-methylcyclohexanones in boiling acetic acid leads to the formation of new 4,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinazolines. The mechanism is discussed. The structure of the products was confirmed by means of 1Н и 13С (DEPTQ) NMR, as well as 2D NMR (NOESY, 1Н–13С HSQC, HMBC).

The reaction of 6-amino-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles with phosphorus sulfide in boiling pyridine leads to the formation of the unexpected [1,2]oxaphosphinino[6,5-c]pyrazoles. The structure of the products was confirmed with 2D Nuclear Magnetic Resonance (NMR) spectroscopy and X-ray analysis.