The reaction of γ-bromoacetoacetanilide with 2-thioxo-1,2-dihydropyridine-3-carbonitriles afforded novel β-ketoamides bearing a heterocyclic fragment, namely 4-(3-cyanopyridin-2-yl)thio-3-oxo-N-phenylbutanamides and 3-(3-aminothieno[2,3-b]pyridin-2-yl)-3-oxo-N-phenylpropanamides. The structure of the reaction products was found to be critically dependent on the reaction conditions: under mild conditions, the S-alkylation products are formed, whereas upon heating in the presence of bases, these intermediates undergo Thorpe–Ziegler isomerization to give the corresponding thienopyridine β-ketoamides. Prolonged heating of the latter leads to further cascade cyclization, affording 4-hydroxythieno[2,3-b:4,5-b']dipyridin-2(1H)-ones. All synthesized compounds were subjected to in silico bioavailability assessment and molecular docking to identify potential protein targets.

A series of previously undescribed 3-amino-4,5,6,7-tetrahydrothieno[2,3-b]pyridines was prepared in 44–79

Unknown 1,3-diaryl-5-(4-arylthiazol-2-yl)hexahydropyrimidine-5-carbonitriles were obtained by the reaction of 2-(4-arylthiazole-2-yl)acetonitriles, aromatic amines and formaldehyde, or one-pot interaction of cyanothioacetamide, phenacylbromides, aromatic amines and formaldehyde in ethanol with high yields (85-95%). The structure of the reaction products was proved using the method of X-ray diffraction analysis.

Introduction: Experimental studies were carried out to determine the antinociceptive activity of new partially hydrogenated pyridines, α-cyanothioacetamide derivatives, in experiments of orofacial trigeminal pain and hot plate test, implemented on white outbred laboratory rats. Materials and Methods: Controlled randomized studies of orofacial trigeminal pain and hotplate were carried out on white outbred laboratory rats in the conditions of the scientificresearch laboratory of Saint Luka Lugansk State Medical University of the Ministry of Health of the Russian Federation. New partially hydrogenated pyridines, α-cyanothioacetamide derivatives(α-CTA) with laboratory codes cv-091, cv-095, cv-099, and cv-142, which are promisingconsidering preliminary studies in silico, were used as test samples. The analgesics metamizolesodium and mefenamic acid were used as comparison drugs. The experiment was implementedon 128 outbred sexually mature male rats. The animals received experimental samples andreference drugs intragastrically. Statistical processing of experimental data was carried out usingthe nonparametric Wilcoxon T-test. The normality of the distribution was determined using the Shapiro-Wilk criterion. Results: According to the data obtained during the experiment, it was determined that newpartially hydrogenated pyridines, α-cyanothioacetamide derivatives, with laboratory codes cv-091, cv-095, cv-099, cv-142, have analgesic activity, which is confirmed by a decrease in the dynamics of the number of scratching movements of the vibrissae area with the front paws in rats, relative to the control group, as well as prolonging the nociceptive response time in the hotplate test. Discussion: In the course of the experimental study, data were obtained indicating thepresence of pronounced analgesic activity in new partially hydrogenated pyridines, α-cyanothioacetamide derivatives (α-CTA). The biological activity of compounds with the lab codescv-091, cv-095, cv-099, and cv-142 is confirmed by data obtained in preliminary studies in silico-biological screening, where the main biological targets that determine the antinociceptiveactivity of the studied compounds are identified. The leading sample in orofacial trigeminal painand hot plate tests is compound cv-099, injected intragastrically at a dosage of 5 mg per kg of animal body weight. Conclusion: New partially hydrogenated pyridines, α-cyanothioacetamide derivatives, showedpronounced antinociceptive activity at a dosage of 5 mg per kg of animal body weight with a single intra-gastric injection in experiments of orofacial trigeminal pain and a hot plate test,which is confirmed by the results obtained during the tests. Compounds with laboratory codescv-091, cv-095, cv-099, cv-142 are recommended for further preclinical studies due to theirpractical prospects.

Previously undescribed nicotinonitrile–coumarin hybrids, namely 2-[2-oxo-2-(2-oxo-2H-chromen-3-yl)ethyl]thiopyridine-3-carbonitriles and -quinoline-3-carbonitriles, were synthesized via the reaction of 2-thioxo-1,2-dihydropyridine-3-carbonitriles with 3-(bromoacetyl)coumarin or 3-(bromoacetyl)benzo[f]coumarin in the presence of sodium propylate. Under laboratory conditions on sunflower seedlings, some of the prepared compounds exhibited a pronounced antidote effect against the herbicide 2,4-D, as well as moderate growth-stimulating activity.

The reaction of 2-((arylamino)methylene)malononitriles with 2-(4-arylthiazol-2-yl)acetonitriles in methanol, mediated by a 1.2-fold excess of sodium methoxide, afforded 3-(arylamino)-2-(4-arylthiazol-2-yl)acrylonitriles in high yields (81–91

Purpose of the study. We aimed to find and study in silico and in vivo novel thienopyridine and dihydropyridine derivatives with hypoglycemic activity. Materials and methods. Three derivatives of thienopyridine and dihydropyridine with potential hypoglycemic effect were selected from 350 novel cyanothioacetamide derivatives synthesized by the authors in the “ChemEx” Research Laboratory using virtual bioscreening based on SwissTargetPrediction software, and their oral administration safety was assessed. During the experimental study conducted on 72 mature male Wistar rats, we modeled hyperglycemia in the animals by means of high-fat diet and dexamethasone load, then we performed pharmacological correction of metabolic disorders with the novel compounds and comparison drugs - Metformin, Vildagliptin. Upon withdrawal of animals from the experiment, blood was sampled for further biochemical investigation and determination of glucose concentration, ALT, AST, total bilirubin, triglycerides, and total blood cholesterol levels. Results. The results of molecular docking showed that the novel compounds with the codes AZ-383, AZ-257, and AZ-020 have putative effects on biotargets with potential for the correction of hyperglycemia and positive impact on lipid metabolism and liver function. In addition, these compounds have a good safety profile when administered orally. In the in vivo study, compounds AZ-383, AZ-257, and AZ-020 were found to have hypoglycemic activity and associated hepatoprotective and hypolipidemic properties. Conclusions. Novel derivatives of thienopyridine and dihydropyridine showed hypoglycemic activity in the experiment following metabolic disorder modeling in animals. This corresponds fully with the biotargets identified in silico for these compounds. Pharmacological activity of compounds with the codes AZ-383, AZ-257, and AZ-020, as well as their oral administration safety confirm the high relevance of further study.

Introduction: Some of the promising classes of chemical compounds for research are 1,4-dihydropyridines, which have potential biological activity and low toxicity. The use of modern technologies for the analysis of substances in silico makes it possible to predict their potential biological effects with a high degree of probability, thereby facilitating further preclinical studies. Materials and Methods: For the purpose of predictive analysis and molecular docking, 6 newcompounds of the 1,4-dihydropyridine group were selected with lab codes SD1-874, F02-104, AS-143, AS-014, AS-144, AS-162. The studied compounds were subjected to predictive analysisin silico. Based on its results, the ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were predicted. PASS Online, Molinspiration Property Calculation Serviceand OSIRIS Property Explorer services were used for predictor analysis. Molecular docking was carried out using the GalaxyWEB Sagittarius service, followed by evaluation of the results usingthe RCSB Protein Data Bank and UniProt Consortium databases. Based on the results of the calculation of physical and chemical parameters, the presence of Lipinski’s criteria was evaluatedin all the samples studied. Results and Discussion: Of the 6 compounds under consideration, the SD1-874 sample haspotential oral activity, according to Lipinski's criteria. Based on the results of predictive analysis in silico, all the studied substances, except SD1-874, are potentially capable of blocking calcium channels. SD1-874 probably has an effect on lipid and carbohydrate metabolism. Evaluating the results of molecular docking, three groups of proteins can be distinguished with which the studied samples can potentially conjugate: a group of proteins that regulate the processes of apoptosis, mitosis, and DNA transcription, a group of proteins that affect blood clotting, and a group that affects the metabolism of lipoproteins, lipids, and glucose. The ability to conjugate with calcium channel subunits is also noted; however, the probability of such an interaction by the molecular docking program is estimated as unlikely. All the studied compounds interact withvarious isoforms of cytochrome P450. Conclusion. According to the results of predictor analysis and the results of molecular docking, among the 6 compounds of 1,4-dihydropyridines selected for analysis, the compound with lab codes SD1-874 is considered the most promising for further study due to the presence of oral bioactivity.

Purpose of the study. The aim of the study was to evaluate the differences in morphometric parameters of the kidneys in rats with longterm administration of nonsteroidal anti-inflammatory drugs and new derivatives of cyanothioacetamide to assess nephrotoxicity. Materials and methods. The new cyanothioacetamide derivatives synthesized at the “ChemEx” Research Laboratory were preliminarily subjected to virtual bioscreening. We selected 5 heterocyclic compounds of cyanothioacetamide derivatives with potential analgesic activity, which was confirmed in various pharmacological tests. To study the chronic effect of new cyanothioacetamide derivatives on the kidneys, rats were preliminarily administered the new compounds intragastrically at a dose of 5 mg/kg for 14 days. The comparison drugs were nimesulide (5 mg/kg), indomethacin (7 mg/kg), acetylsalicylic acid and paracetamol at a dose of 50 mg/kg. The stereometric indices of the kidneys were assessed in each group. Results. The study revealed that new cyanothioacetamide derivatives with laboratory codes d02–123, d02–133, d02–139, d02–172, d02–149 have lower nephrotoxicity compared to reference drugs. In particular, the compound with the code d02–149 showed minimal changes in the structure of the proximal and distal tubules and the absence of hemorrhages, indicating its low risk for the kidneys. Derivatives d02–123 and d02–133 showed adaptive changes, such as an increase in the area of the distal tubules and a decrease in the volume of normal glomeruli, which may be associated with compensatory mechanisms during long–term exposure. Conclusions. New cyanothioacetamide derivatives demonstrate potentially less nephrotoxic effects compared to existing NSAIDs. These results highlight the need for further study of new cyanothioacetamide derivatives to develop safer drugs with analgesic activity, especially given the ability of some of them to have less damaging effects on the kidneys.

The inflammatory process accompanies most of the pathologies and requires pharmacological correction. In spite of significant achievements of scientists in the field of medicine and pharmacology, existing steroid and nonsteroidal antiinflammatory drugs have a number of undesirable reactions. To date, one of the most urgent directions is the search for new effective and safe drugs with anti-inflammatory activity. The aim of the study was to investigate the anti-exudative properties of new 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives in the classical test of acute formalin edema. Material and methods. The study was conducted on 88 white rats weighing 210–250 g. The effectiveness of compounds was determined in a model of acute formalin edema, which was induced by subplantar injection of 0.1 ml of 2 % formalin solution into the right hind limb of the animals. The severity of exudation was evaluated oncometrically in comparison with reference drugs – ibuprofen, indomethacin, meloxicam and metamizole sodium. The studied substances were administered intragastrically at a dose of 5 mg/kg 1.5 hours before the induction of inflammation. Results. It was found that some compounds exhibit anti-exudative activity, more pronounced or similar to the activity of reference drugs. The laboratory sample with code mar-137 was the leading sample and outperformed the comparators; 24 hours after the modeling of edema, it exceeded ibuprofen (by 2.39 %), metamizole sodium (by 4.77 %) in anti-exudative efficacy and had an anti-inflammatory effect similar to the activity of indomethacin and meloxicam. Conclusions. Newly synthesized laboratory samples of 3-cyano-1,4-dihydropyridines, cyanothioacetamide derivatives, were found to exhibit pronounced anti-exudative activity and are of interest for further research as a new class of anti-inflammatory drugs.

The reaction of (2E)-3-aryl-2-(4-aryl-1,3-thiazol-2-yl)acrylonitriles with an excess of nitric acid in AcOH proceeds regioselectively to afford previously unknown (2E)-3-aryl-2-(4-aryl-5-nitro-1,3-thiazol-2-yl)acrylonitriles in 82–96

New approaches based on multicomponent condensation reactions were proposed to the synthesis of new heterocyclic derivatives of malononitrile dimer of the series of 7-oxa-1,3,6-triazabenzo[no]tetraphene, 1,2,3,4-tetrahydropyrazolo[1,5-a][1,3,5]triazine, 1,3,5,5-tetracyanocyclohex-3-ene, 3,9-diazaspiro[5.5]undeca-1,4-diene and 1Н,5Н-spiro[3,7-diazabicyclo[3.3.1]non-2-ene-9,4'-piperidine]. Structure of the products was studied using mass spectrometry, IR and NMR spectroscopy, as well as X-ray diffraction analysis.

New hybrid molecules bearing 4-(2-furyl)-1,4-dihydronicotinonitrile and 4-(2-furyl)-1,4,5,6-tetrahydronico- tinonitrile fragments were prepared starting from cyanothioacetamide and furfural. The hypoglycemic activity in dexamethasone-induced diabetes mellitus was investigated in vivo in senile rats. Some compounds revealed hypoglycemic effects superior to that of the reference drug (metformin).

Introduction: To solve the problem of complex and safe pharmacological correction of metabolic disorders, including hyperlipidemia, hyperglycemia, and liver lesions is currently very important. With this in mind, the new derivatives of cyanothioacetamide with a dihydropyridine framework, with a potential effect on lipid and carbohydrate metabolism and the functioning of the liver are of great interest. Materials and Methods: To conduct an experiment, three samples were selected from an extensive library of new cyanothioacetamide derivatives, which, according to in silico studies, proved promising towards the positive effect on lipid and carbohydrate metabolism, as well as towards the protective effect on the liver. To study the compounds in vivo, metabolic disorders were simulated in Wistar rats by long -term alimentary and subsequent dexamethasone loads. The pharmacological efficacy of new compounds AZ-383, AZ-257, AZ-020 (administered in a dose of 1 mg/kg for 14 days) was assessed in comparison with metformin (300 mg/kg for 14 days) and vildagliptin (8 mg/kg for 14 days) by determining the biochemical indicators of blood (ALT, AST, total bilirubin, total cholesterol, triglycerides, and glucose), morphological and morphometric studies of the liver sections, and the study of immunohistochemical indicators of hepatocyte proliferation. The experimental results were statistically processed using the recognized methods of mathematical statistics. When processing the experimental data, the average arithmetic (AA) was determined. The statistical significance of the compared options was determined on the basis of the Student’s t-test, with the critical value of the Student’s t-test equal to 2.101 and the significance level α = 0.05. Results: The study shows that all the new compounds studied in the experiment – AZ-383, AZ-257, AZ-020 – have hypolipidemic and hepatoprotective properties, which manifested in the reduced levels of liver biochemical markers of blood, which had increased after simulating metabolic disorders, in the reduced concentration of total cholesterol and triglycerides in blood, in the normalization of liver microarchitecture, as well as in the proliferative activity of hepatocytes. Discussion: The hepatoprotective and hypolypidemic properties of the new derivatives of cyanothioacetamide with a dihydropyridine framework, which were determined while conducting the experiment, can be accounted for by their effects on the biotargets, identified for AZ-383, AZ-257, and AZ-020 in silico. According to the results, the most pronounced hepatoprotective activity was found in AZ-383 (intragastrically, 1 mg/kg for 14 days). The Ki-67 proliferation index under the influence of this compound was registered at the level of 1.48±0.03%, which exceeds this indicator in the control animals and proves a significant hepatoprotective activity of AZ-383. Conclusion: The results show good prospects and high efficacy of the new studied cyanothioacetamide derivatives, such as AZ-383, AZ-257, AZ-020 (in a dose of 1 mg/kg), in terms of comprehensive correction of metabolic disorders. Further study is needed for this class of compounds.

Iodination of 2-(4-arylthiazole-2-yl)acetonitriles in DMF proceeds with the formation of previously undescribed 2,3-bis(4-aryl-1,3-thiazole-2-yl)but-2-enedicarbonitriles as a mixture of E- and Z-isomers. The latter were alternatively prepared by the reaction of cyanothioacetamide, α-bromoketones and iodine in DMF. Structure of the key compounds was proven by means of single crystal X-ray diffraction analysis.

Objective: to identify the relationship between the results of in silico and in vivo studies of hypoglycemic, hypolipidemic, and hepatoprotective properties expressed by a new 1,4-dihydropyridine derivative with the laboratory code AZ-383. Material and Methods. Virtual biological screening of the AZ-383 compound was conducted using SwissTargetPrediction online tool. The identified biotargets were promising for pharmacological correction of multiple metabolic disorders, which was confirmed in an in vivo experiment conducted on male Wistar rats: the levels of glucose, total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, and total bilirubin in the blood were examined; the microarchitecture of the rat liver was assessed after pharmacological correction (using the AZ-383 compound) of the modeled metabolic disorders. Results. The presence of hypoglycemic, hypolipidemic and hepatoprotective properties in the compound AZ-383, along with its favorable effect on body weight, was revealed. The glucose level reached values of 7.9±0.4 mmol/L. The body weight of rats after the use of AZ-383 was 378±12 g. Under the influence of AZ-383, we observed an increase in the number of hepatocytes by 17.8%, a reduction in the size of hepatocytes by 7%, and a decrease in the area of the cytoplasm and nuclei of hepatocytes by 5.2% and 18.7%, respectively, vs. the control group of animals. Conclusion. Our in vivo experimental study confirmed the presence of hypoglycemic, hypolipidemic and hepatoprotective properties in the AZ-383 compound, which corresponds to the biotargets determined in silico for this 1,4-dihydropyridine derivative.

N-Methylmorpholinium 4-aryl-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolates reacted with hydrogen sulfide and formaldehyde in ethanol to give 5-aryl-4-sulfanylidene-2,3,4,5,6,8-hexahydro-7H-pyrido[3,2-e][1,3]thiazin-7-ones. The molecular and crystal structures of N-methylmorpholinium 5-cyano-2-oxo-4-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydropyridine-6-thiolate were determined by X-ray analysis.

Introduction. On the basis of the Chemex Scientific Lab of the Vladimir Dahl Lugansk State University we have synthesized and selected 4 samples of partially hydrogenated pyridine derivatives via in silico screening, containing a furan fragment in the fourth position (codenamed cv-150, cv-140, cv-083 and jen09-039), the effect of which on the course of dexamethasone-induced diabetes mellitus (DM) is of interest. Aim. To study the morphological parameters of the liver of dexamethasone-induced diabetic rats during a period of pronounced senile changes in the setting of pharmacological treatment with new partially hydrogenated pyridines, cyanothioacetamide derivatives. Materials and methods. The experiment was carried out with 92 18-month-old albino male rats, by administering per os 4 samples of 1,4-dihydropyridine at a dose of 1 mg/kg to each individual group of animals with dexamethasone-induced diabetes mellitus. Simultaneously, a control group (dexamethasone-induced diabetes) and a group of intact animals (without steroid-induced diabetes) were used. Dexamethasone was administered for 13 days. The intact and control group of animals consisted of 12 individuals. Four experimental groups of animals consisted of 17 individuals in each group. Animals of the experimental groups received one of the study compounds cv-150, cv-140, cv-083 and jen09-039 via gastric tube at a dose of 1 mg/kg body weight for 21 days. Results. During the experiment, 10 animals died from late complications of DM. Death was recorded in the control and experimental groups treated with cv-083 and jen09-039 compounds. The most pronounced hepatomegaly was found in animals of the control group, the absolute liver weight averaged 16.43 g (3.4% of body weight) with indicators in intact animals group of 14.44 g (2.8% of body weight). The liver weight of rats treated with the cv-150 compound was 12.90 g (2.74% of body weight). The minimal number of pathological changes of the liver was detected in animals receiving partially hydrogenated pyridine cv-083 – 28.6%. The maximum number of pathological changes was registered in control animals receiving dexamethasone without pharmacological treatment – 88.9%. No liver changes were detected in intact rats. Conclusion. Positive metabolic and psychosomatic changes were observed during the experiment in groups of animals treated with cv-150 and cv-140 compounds. There was no mortality in these experimental groups. According to necroptic study, hepatoprotective activity was found in these compounds. The result of using the cv-083 compound is questionable. The jen09-039 compound did not have any positive effect on the course of dexamethasone-induced diabetes.

The antinociceptive activity of new derivatives of α-cyanothioacetamide was evaluated in the formalin test, which reflects an acute inflammatory reaction. For the study, a standard model of an acute inflammatory reaction was used: laboratory animals were subplantarly injected with 0.1 ml of 5% formalin (algogen) into the right hind limb. The α-cyanothioacetamide samples studied were injected intragastrically at 1 ml at a dose of 5 mg/kg 1.5 hours before the experiment. The comparison drug was chosen as Analgin JSC "Pharmstandard" at a dose of 7 mg/kg. For one hour after injection, the number of pain reactions was recorded according to the method of 4 types of behavioral response. We have identified the potential antinociceptive activity of new derivatives of α-cyanothioacetamide, which allows them to be used for a detailed study.