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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.

The Michael addition reaction between dithiomalondianilide (N,N′-diphenyldithiomalondiamide) and arylmethylidene Meldrum’s acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

The Michael addition reaction between dithiomalondianilide (N,N′-diphenyldithiomalondiamide) and arylmethylidene Meldrum’s acids, accompanied by subsequent heterocyclization, was investigated along with factors affecting the mixture composition of the obtained products. The plausible mechanism includes the formation of stable Michael adducts which, under the studied conditions, undergo further transformations to yield corresponding N-methylmorpholinium 4-aryl-6-oxo-3-(N-phenylthio-carbamoyl)-1,4,5,6-tetrahydropyridin-2-thiolates and their oxidation derivatives, 4,5-dihydro-3H-[1,2]dithiolo[3,4-b]pyridin-6(7H)-ones. The structure of one such product, N-methylmorpholinium 2,2-dimethyl-5-(1-(2-nitrophenyl)-3-(phenylamino)-2-(N-phenylthiocarbamoyl)-3-thioxopropyl)-4-oxo-4H-1,3-dioxin-6-olate, was confirmed via X-ray crystallography.

Noncatalyzed, regio- and stereoselective hypochlorite oxidation of 3-aminothieno[2,3-b]pyridine-2-carboxamides is presented. Unexpectedly, the oxidation proceeded by different mechanistic pathways, and different products were formed, depending on the nature of solvents used. A possible mechanism, the structure of products, kinetics and dynamics of intramolecular processes, and biological activity of products are discussed.

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.

[Cu(L)2] (1), [Co(L)2] (2), [Ni(L)2]·H2O (3) complexes where L is 2-{[(2-methoxyphenyl)amino]methylene}-5,5-dimethyl-cyclohexane-1,3-dionate are synthesized. Single crystals of complexes 1-3 are obtained. According to X-ray crystallographic data, in the Co and Ni complexes, a coordination polyhedron N2O4 is a distorted octahedron, and in the Cu complex, N2O2 is a distorted square. L is a tridentate ligand coordinated by oxygen atoms of carbonyl and methoxy groups as well as the nitrogen atom of the amide group. The cytotoxic properties of 2-{[(2-methoxyphenyl)amino]methylene}-5,5-dimethyl-cyclohexane-1,3-dione and respective complexes are studied on the Hep2 cell line (human laryngeal carcinoma). The compounds are shown to not exhibit cytotoxic properties in the studied concentration range (1-50 μM). Antibacterial, protistocidal, and fungistatic properties of HL, its structural analogue 2-anilinomethylidene-5,5-dimethylcyclohexane-1,3-dione (HL1), and complexes on their base are also studied. The antibacterial activity of HL and [Co(L1)2(C2H5OH)2] against S. aureus, of HL1 and [Co(L)2] against E. coli is revealed within 25-30% of the activity of reference drugs (ciprofloxacin, furazolidone). The [Ni(L1)2(C2H5OH)2] complex is found to have a pronounced protistocidal activity. Furthermore, the behavior of the [Ni(L)2]·H2O complex in phosphate buffered saline is analyzed at storage times t = 0 h, 24 h, 48 h and also in an aqueous solution at different pH values.

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 recent data (2007–2018) on the synthesis of thieno[2,3-b]pyridines are summarized and systematized.

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.

Cascade reaction of 2 equiv. of furfural (or equimolar amounts of furfural and aromatic aldehyde) with secondary amines and ethyl cyanoacetate afforded diethyl esters of 8-(dialkylamino)-3-aryl-6-oxo-2,4-dicyanobicyclo[3.2.1]octane-2,4-dicarboxylic acids with yields of 37–54%. Antimicrobial activity of a number of obtained compounds in vitro was studied, and biological activity in silico was analyzed. The obtained bicyclo[3.2.1]octanes are inactive or exhibit weak fungicidal activity, but exhibit moderate bactericidal effect.

Hydroxymethylation of (E)-3-aryl-2-cyanoprop-2-enethioamides with an aqueous alcoholic solution of formaldehyde has afforded (E)-3-aryl-N-(hydroxymethyl)-2-cyanoprop-2-enethioamides. The predictive analysis of the biological activity of the obtained compounds in silico has been carried out.

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.

The reaction of cyanothioacetamide with ethoxymethylenemalonate and triethylamine in ethanol upon heating is non-selective and leads to the formation of a mixture of triethylammonium 1,5-diamino-2,4-dicyano-5-thioxopenta-1,3-diene-1-thiolate and triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate with a predominance of the latter. When treating with primary amines and 37% formalin in boiling aqueous alcohol, the reaction product gives only 4-(1,3,5-thiadiazinan-2-ylidene)-2-(3,4-dihydro-2H-1,3,5-thiadiazin-6-yl)pent-2-enedinitrile instead of the expected pyrido[2,1-b][1,3,5]thiadiazine derivatives. Triethylammonium 6-oxo-3-cyano-5-ethoxycarbonyl-1H-pyridin-2-thiolate does not react under these conditions.

Terminal polychlorides of hyperbranched polyester polyol Boltorn H20 were synthesized. Subsequent treatment of the resultant polychlorides with absolute pyridine or triphenylphosphine led to the formation of products of varying degrees of functionalization, containing pyridinium or triphenylphosphonium moieties in terminal positions.

The reaction of 5-acetyl-4-aryl-6-hydroxy-3,6-dimethyl-4,5,6,7-tetrahydroindazoles p-toluenesulfonyl chloride in boiling acetone in the presence of triethylamine was found to occur in a completely regioselective with the exclusive formation of 5-acetyl-4-aryl-6-hydroxy-3,6-dimethyl-1-(4-methylbenzenesulfonyl)-4,5,6,7-tetrahydroindazoles. The experimental results were confirmed by quantum chemical calculations. In silico biological activity evaluation of the synthesized compounds was performed.

The microreview summarizes the data on heterocyclization methods leading to the formation of isoxazolo[5,4-b]-pyridines published over the last 5 years. The material is classified according to the method of constructing the isoxazolopyridine system.

This microreview summarizes new data (2014–2019) on the use of 1-cyanoacetyl-3,5-dimethylpyrazole in organic synthesis.

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.

3-Aminothieno[2,3-b]pyridine-2-carboxylic acid esters readily reacted with 3,5-dimethyl-1-(cyanoacetyl)-1H-pyrazole to give previously unknown N-(thieno[2,3-b]pyridin-3-yl)cyanoacetamides. Reactions of the latter with 2-(arylmethylidene)malononitriles were nonselective, and mixtures of different heterocyclization products were generally formed. The cyclization of ethyl 4,6-dimethyl-3-[(cyanoacetyl)amino]thieno[2,3-b]-pyridine-2-carboxylate afforded 2,4-dihydroxy-7,9-dimethylthieno[2,3-b : 4,5-b′]dipyridine-3-carbonitrile whose tautomeric equilibrium was studied by DFT quantum chemical calculations. In silico analysis of biological activity of the synthesized compounds was performed.

Introduction. In the modern world people are exposed to the influence of adverse psychological and physical factors, escalating in intensity. The search for new pharmacodynamic effects of [1,3,5]-thiadiazine derivatives designated by significant biological activity of these compounds is an essential issue.Aim. To research adaptogenic activity of tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivatives using a modified Porsolt Forced Swim Test.Materials and methods. Four substances from the group of 3-R-8-aryl-6-oxo-3,4,7,8-tetrahydro-2H,6Hpyrido[2,1-b][1,3,5]thiadiazine-9-carbonitriles were selected for the research. Rats were divided into a control group, 5 reference groups (amitriptyline, caffeine, thiotriazolin, thiocetam, ginseng) and 4 experimental groups according to the number of the studied original tetrahydropyrido[2,1-b][1,3,5] thiadiazine derivatives.Results. Intragastric injection of substance 2 for 5 days in the modified forced swim test (forced swimming with freight) increased work capacity and endurance of the rats by 103.42% as opposed to the initial results. The detected adaptogenic activity of this tetrahydropyrido[2,1-b][1,3,5]thiadiazine derivative six times exceeds adaptogenic activity of ginseng and seven times that of amitriptyline. The rats in the control group were active for a bit longer time. Ginseng raised the time of activity by 17% at day 5. Caffeine essentially reduced work capacity and endurance. Amitriptyline showed adaptogenic activity at day 3 of the research (increase by 10.4%). Thiotriazolin also showed adaptogenic activity on day 3 of the research (increase by 30.17%). Thiocetam increased the time of activity by 78.55%. Substance 4 had adaptogenic activity too; it increased the time of activity in aversive conditions by 58.25%, which three times exceeds this parameter for ginseng and four times for amitriptyline.

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.

The review summarizes the results obtained by our research group over the past 15 years in chemistry of N-, S,N-, and Se,N-heterocycles resulted from aminomethlation of a wide range of acyclic and heterocyclic substrates derived from active methylene amides, thioamides, and selenoamides. A series of 1,3,5-thia(selena)diazines, 3,7-diazabicyclo[3.3.1] nonanes, 3,5,7,11-tetraazatricyclo[7.3.1.02,7]tridec-2-enes, 1,3,5,7-tetrazocines, and pyrido[1,2-a][1,3,5]triazines were synthesized. The general regularities of the Mannich reaction in the series of N-, S,N-, and Se,N-containing pyridine substrates were discussed. Biological activities of some synthesized compounds were studied to reveal compounds with antiviral, analeptic, anti-inflammatory, and antipyretic activities.

The oxidation of 3-aminothieno[2,3-b]pyridine-2-carboxamides with commercially available bleach leads to the formation of dimeric pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridines (7a,14a-diamino-7,14-bis(aryl)-7,7a,14,14a-tetrahydro-6H,13H-pyrido[3″″,2″″:4‴,5‴]thieno[2‴,3‴:4″,5″]pyrrolo-[3″,4″:3′,4′]pyrrolo[2′,3′:4,5]thieno[2,3-b]pyridine-6,13-diones) in moderate yields (37–52%).

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.

N,N′-diphenyldithiomalonamide (dithiomalondianilide) smoothly reacts with various Michael acceptors to give either stable Michael adducts or products of their further heterocyclization. The structure of the products was confirmed by 2D NMR experiments and X-ray data. The mechanisms of the reactions are discussed.

Easily available 2-(bis(alkylthio)methylene)malononitriles react with cyanoacetamide or cyanothioacetamide to give 4-(alkylthio)-6-amino-2-oxo(thioxo)-1,2-dihydropyridine-3,5-dicarbonitriles. Upon treatment with primary amines and/or HCHO, the compounds undergo heterocyclization to afford new pyrido[1,2-a][1,3,5]triazines or ring-condensed 1,3,5,7-tetrazocine derivatives.

Benzofuroxane reacts under Beirut reaction conditions with active methylene nitriles to give new 2-aminoquinoxaline-1,4-dioxides. The treatment of known 2-amino-3-cyanoquinoxaline-1,4-dioxide with chloroacetyl chloride afforded corresponding chloroacetamide which is useful for the preparation of various heterocycles bearing a quinoxaline-1,4-dioxide core system.

The reaction of 4-methyl-2,6-dichloronicotinonitrile with malononitrile dimer (2-amino-1,1,3-tricyanopropene) in the presence of triethylamine leads to regioselective nucleophilic substitution of the chlorine atom at position 6 and the formation of triethylammonium 2-amino-3-(4-methyl-6-chloro-5-cyanopyridin-2-yl)-1,1,3-tricyanoprop-2-en-1-ide. The structure of the product was confirmed by X-ray studies.

5-Amino-3-(cyanomethyl)-1H-pyrazole-4-carbonitrile, prepared by reaction of malononitrile dimer with hydrazine, smoothly reacts with chloroacetyl chloride to form 2-chloro-N-(4-cyano-3-(cyanomethyl)-1H-pyrazol-5-yl)acetamide in good yield. The latter easily reacts with 3-cyanopyridine-2-thiolates to give hybrid molecules bearing nicotinonitrile and pyrazole units.

New triethylammonium 6-amino-4-aryl-3-carbamoyl-5-cyano-1,4-dihydropyridine-2-thiolates were prepared in good yields by ternary condensation of malononitrile, aldehydes and monothiomalonamide (3-amino-3-thioxopropanamide) in the presence of Et3N. The thiolates undergo S-alkylation under mild conditions to give new 1,4-dihydronicotinamides. Molecular docking studies were carried out in order to explore the interaction mechanism and to investigate suitable binding modes of the new compounds on the calcium channel proteins. Some of the compounds in experiments in silico were found to be more potent as calcium channel blockers than reference drug Nifedipine.

Here, 1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles, prepared by the reaction of cyanoacethydrazide with arylmethylene malononitriles, react with 1-cyanoacetyl-3,5-dimethylpyrazole and chloroacetyl chloride to give corresponding cyanoacetamides and chloroacetamides. The reaction with phthalic anhydride proceeds under harsh conditions to give 4,7-dioxo-4,7-dihydropyrido[1′,2′:2,3][1,2,4]triazolo[5,1-a]isoindole- 1,3-dicarbonitriles.