The reaction of monothiomalonamide with aromatic aldehydes and Meldrum’s acid in the presence of triethylamine yielded previously unknown stable Michael adducts – triethylammonium 5-[3-amino-1-(het)aryl-3-oxo-2-(thiocarbamoyl)propyl]-2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-olates in 64–83

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 design of molecular hybrids based on biologically active molecules is one of the most prominent strategies in modern drug design. Molecular hybridization involves combining two or more pharmacophore fragments into a single molecule, resulting in synergistic effects and combination therapy within a single multifunctional agent. These hybrids often exhibit more specific and potent activity compared to classical drugs. In this study, we developed a method for synthesizing new molecular hybrids of 2-iminothiazoline/3-cyanoquinoline and 2-iminothiazoline/3-aminothieno[2,3-b]quinoline through the reaction of N-(3-aryl-4-phenylthiazol-2(3H)-ylidene)2-chloroacetamides with 4-aryl-2-thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles. The starting 4-aryl-2thioxo-1,2,5,6,7,8-hexahydroquinoline-3-carbonitriles were synthesized by reacting aromatic aldehydes, cyanothioacetamide, and 4-(cyclohex-1-en-1-yl)morpholine. Meanwhile, the novel alkylating agents, N-(3-aryl-4phenylthiazol-2(3H)-ylidene)-2-chloroacetamides, were prepared in 66-73 % yield via a two-step process: 1) Heterocyclization of alpha-thiocyanatoacetophenone with primary aromatic amines in the presence of aqueous HCl; 2) Subsequent reaction of the resulting 3-aryl-4-phenylthiazol-2(3H)-imines with chloroacetyl chloride in anhydrous benzene. The target molecular hybrids - 2-iminothiazoline/3-cyanoquinoline and 2-iminothiazoline/3-aminothieno [2,3-b]quinoline - were isolated in yields of 64-93 % and 63-92 %, respectively. The structures of the new hybrids were thoroughly characterized using X-ray diffraction analysis, FTIR spectroscopy, and NMR spectroscopy, including 2D NMR techniques (1H-13C HSQC, 1H-13C HMBC). An unusual feature in the FTIR spectra - the absence of nu(C--O) absorption bands above 1600 cm-1 - was attributed to conjugation between the carbonyl group and either the 2-iminothiazoline C--N fragment or the thieno[2,3-b]quinoline moiety. These findings were further supported by quantum-chemical calculations. Both computational and X-ray data indicated that the most stable conformation for 3-amino-4-aryl-N-(3-aryl-4-phenylthiazol-2(3H)-ylidene)-5,6,7,8-tetrahydrothieno[2,3b]quinoline-2-carboxamides is the s-cis conformation, stabilized by an intramolecular hydrogen bond between the NH2 protons and the C--O oxygen. Additionally, six new compounds demonstrated a noticeable antidote effect against the herbicide 2,4-D in field experiments on sunflower seedlings.

New [1,2]dithiolo[3,4-b]pyridine-5-carboxamides were synthesized through the reaction of dithiomalondianilide (N,N′-diphenyldithiomalondiamide) with 3-aryl-2-cyanoacrylamides or via a three-component reaction involving aromatic aldehydes, cyanoacetamide and dithiomalondianilide in the presence of morpholine. The structure of 6-amino-4-(2,4-dichloro- phenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxamide was confirmed using X-ray crystallography. To understand the reaction mechanism in detail, density functional theory (DFT) calculations were performed with a Grimme B97-3c composite computational scheme. The results revealed that the rate-limiting step is a cyclization process leading to the closure of the 1,4-dihydropyridine ring, with an activation barrier of 28.8 kcal/mol. Some of the dithiolo[3,4-b]pyridines exhibited moderate herbicide safening effects against 2,4-D. Additionally, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) parameters were calculated and molecular docking studies were performed to identify potential protein targets.

Oxidation of (Е)-3-aryl-2-cyanothioacrylamides under the action of the Et2S(O)–HCl system leads to the formation of (2Е,2′E)-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis[3-arylacrylonitriles] in 54–91

Oxidation of ( Е )-3-aryl-2-cyanothioacrylamides under the action of the Et2S(O)-HCl system leads to the formation of (2 Е ,2' E )-2,2'-(1,2,4-thiadiazole-3,5-diyl)bis[3-arylacrylonitriles] in 54-91% yields. Structure of the obtained compounds was confirmed by the two-dimensional NMR spectroscopy data. A plausible reaction mechanism was discussed. Two compounds showed a pronounced antidote effect against 2,4-D herbicide in a laboratory experiment on sunflower seedlings in the absence of growth-stimulating activity.

The reaction between dithiomalondianilide (N,N’-diphenyldithiomalondiamide) and alkyl 3-aryl-2-cyanoacrylates in the presence of morpholine in the air atmosphere leads to the formation of alkyl 6-amino-4-aryl-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]- pyridine-5-carboxylates in 37–72% yields. The same compounds were prepared in 23–65% yields by ternary condensation of aromatic aldehydes, ethyl(methyl) cyanoacetate and dithiomalondianilide. The reaction mechanism is discussed. The structure of ethyl 6-amino-4-(4-methoxyphenyl)-7-phenyl-3-(phenylimino)-4,7-dihydro-3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylate was confirmed by X-ray crystallography. Two of the prepared compounds showed a moderate growth-stimulating effect on sunflower seedlings. Three of the new compounds were recognized as strong herbicide safeners with respect to herbicide 2,4-D in the laboratory and field experiments on sunflower.

The reaction of (1-ethoxyethylidene)malononitrile with cyanoacetamide or cyanothioacetamide has yielded 6-amino-4-methyl-2-(thio)oxo-1,2-dihydropyridine-3,5-dicarbonitriles. The resulting pyridine derivatives enter into the aminomethylation reaction with an excess of formaldehyde and primary amines with the formation of previously unknown 8-methyl-6-oxo-3-R-1,3,4,6-tetrahydro-2H-pyrido[1,2-a][1,3,5]triazine-7,9-dicarbonitriles. Further treatment of 6-amino-4-methyl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile and its oxygen analog with excess of formaldehyde has led to the formation of 3,10-dimethyl-1,8-dithioxo-5,6,12,13-tetrahydro-1H,8H-dipyrido[1,2-a:1′,2′-e][1,3,5,7]tetrazocin-2,4,9,11-tetracarbonitrile and 6,6′-[methylenedi(imino)]bis(4-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile), respectively. These compounds have shown a pronounced antidote effect against the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid) in laboratory and field experiments on sunflower seedlings. Furthermore, 6-amino-4-methyl-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile has exhibited pronounced anticorrosion properties, acting as an adsorption-type corrosion inhibitor. The mechanism of the anticorrosion action has been investigated in detail using X-ray photoelectron spectroscopy.

A new method was proposed for the preparation of 5-amino-3-(cyanomethyl)-1 H -pyrazole-4-carbonitrile by reaction of the potassium salt of malononitrile dimer with hydrazinium sulfate. The reaction of 5-amino-3(cyanomethyl)-1 H -pyrazole-4-carbonitrile with aromatic aldehydes in the presence of catalytic amounts of morpholine leads to the formation of Knoevenagel condensation products. Aminomethylation of the resulting ( Z )-5-amino-3-(2-aryl-1-cyanovinyl)-1 H -pyrazole-4-carbonitriles with primary aromatic amines and excess aqueous HCHO in refluxing DMF leads to the formation of 7-(2-aryl-1-cyanovinyl)-1,2,3,4-tetrahydropyrazolo[1,5- a ][1,3,5]triazine-8-carbonitriles. Bioavailability parameters were studied in silico , and possible protein targets were predicted by protein-ligand docking. In an in vitro experiment on cultures of E. coli , S. aureus and B. pumilis , 5-amino-3-(cyanomethyl)-1 H -pyrazole-4-carbonitrile does not show any noticeable antibacterial effect. At the same time, three compounds of the pyrazolo[1,5- a ][1,3,5]triazine series showed a pronounced antidote effect against the herbicide 2,4-D on sunflower seedlings in a laboratory experiment, for one compound a noticeable growth-stimulating effect was noted.

One-pot reaction of cyanothioacetamide, N-(2,4-dichlorophenyl)acetoacetamide and furfural in the presence of excessive N-methylmorpholine in EtOH at 25 °C gives N-methylmorpholinium 5-[(2,4-dichlorophenyl)carbamoyl]-3-cyano-4-(2-furyl)-6-methyl-1,4-dihydropyridin-2-thiolate, yielding 82%. Subsequent S-alkylation of the prepared thiolate with N-substituted α-chloroacetamides occurs in a regiospecific way to form N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-[(2-oxo-2-{[substituted aryl]amino}ethyl)sulfanyl]-1,4-dihydropyridin-3-carboxamides 10–17. Compounds 10–17 were identified by means of IR and NMR spectroscopy, as well as by elemental analysis. Synthesized compounds 10–17 were examined for anti-exudative and anti-inflammatory activity. White laboratory rats numbering 112 individuals were divided into control (“acute formalin-induced paw edema”) and intact groups, 4 reference groups (acetylsalicylic acid, indomethacin, nimesulide, and paracetamol) and 8 experimental groups, according to the number of tested 1,4-dihydropyridine derivatives. The efficacy of the anti-inflammatory activity of the samples was evaluated in the model of “acute formalin paw edema” in rats, which was simulated by injecting 0.1 mL of 2% formalin solution into the aponeurosis of the right hind limb. The studied compounds were given intragastrically at a dose of 5 mg/kg 1.5 hours before the induction of the inflammatory process. Oncometric changes were measured quantitatively by limb girth. It was shown that the most pronounced anti-inflammatory activity was possessed by: N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-[(2-oxo-2-{[3-(trifluoromethyl)phenyl]-amino}ethyl)sulfanyl]-1,4-dihydropyridin-3-carboxamide 12 (1.09–1.81 times more effective than the reference drugs); 6-[(2-anilino-2-oxoethyl)sulfanyl]- N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-1,4-dihydropyridin-3-carboxamide 16, which reduced the induced paw edema by 42.91% compared to control; N-(2,4-dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-({2-[(3-methylphenyl)amino]-2-oxoethyl}sulfanyl)-1,4-dihydropyridin-3-carboxamide 14 (1.65–2.85 times higher anti-inflammatory activity compared to the reference drugs in 18-hour experiments). N-(2,4-Dichlorophenyl)-5-cyano-4-(2-furyl)-2-methyl-6-({2-[(3,5-dimethylphenyl)amino]-2-oxoethyl}sulfanyl)-1,4-dihydropyridin-3-carboxamide 11 was found to be the most active, reducing paw edema 2.9 times more effectively than nimesulide

Electrochemical oxidation of (Е)-3-aryl-2-cyanoprop-2-enethioamides in a undivided cell in the presence of KBr in an aqueous or aqueous-organic medium has led to the formation of (2Е,2′E)-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis[3-arylacrylonitriles] in 37–76

( E )-3-Aryl-2-cyanoprop-2-entioamides, prepared by Knoevenagel condensation between aromatic aldehydes and cyanothioacetamide, react with sodium nitrite in acetic acid to form (2 E ,2′ E )-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis[3-arylacrylonitriles]. A possible mechanism and limitations of the reaction are discussed. Molecular docking was carried out in order to search for possible protein targets for the obtained 1,2,4-thiadiazoles. One of the compounds showed a pronounced antidote effect against the herbicide 2,4-D in a laboratory experiment on sunflower seedlings and under field conditions.

The (2E,2′E)-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis[3-aryl(hetaryl)-2-cyanoprop-2-entioamides] were obtained by treating (E)-3-aryl(hetaryl)-2-cyanoprop-2-entioamides or their [4 + 2] dimerization products, 6-amino-2,4-diaryl-3,5-dicyano-3,4-dihydro-2H-thiopyran-3-carbothioamides, with bromine or iodine in DMF. The scope and limitations of the reaction are discussed. Partial ring bromination of starting thioamide was observed only in the case of (E)-2-cyano-3-(4-hydroxy-3-methoxyphenyl)prop-2-enethioamide. When treated with bromine in DMF, 2-cyano-2-cyclopentylideneethanthioamide gives 2,2′-(1,2,4-thiadiazole-3,5-diyl)bis[2-cyclopentylideneacetonitrile] in 69% yield. When 2-imino-7-methoxy-2H-chromene-3-carbothioamide was brominated, 3a,4-dibromo-7-methoxy-3a,4-dihydro-3H-chromeno[2,3-c]isothiazol-3-iminium bromide was isolated instead of the expected 3,3′-(1,2,4-thiadiazole-3,5-diyl)bis(7-methoxy-4a,8a-dihydro-2H-chromene-2-one). The structure of (2E,2′E)-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis{3-[2-(trifluoromethyl)phenyl]acrylonitrile} was confirmed by X-ray studies. Molecular docking was performed in order to find possible protein targets for the prepared new 1,2,4-thiadiazoles. One of the compound, ((2E,2′E)-2,2′-(1,2,4-thiadiazole-3,5-diyl)bis(3-(4-chlorophenyl)acrylonitrile), showed good herbicide safening effect in the experiments with sunflower seedlings.

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.

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 acetylenic ketones with cyanothioacetamide in the presence of morpholine yields 4,6-disubstituted 2-thioxo-1,2-dihydropyridine-3-carbonitriles. Structure of the obtained compounds was proved using 2D NMR spectroscopy, as well as transformations into 3-aminothieno[2,3-b]pyridine-2-carboxamide derivatives.

A series of functionalized 3-(substituted amino)thieno[2,3-b]pyridines bearing azidoacetamide and monothiooxamide fragments have been prepared starting from readily available 2-chloro-N-(thieno[2,3-b]pyridine-3-yl)acetamides. Some of the compounds proved to be strong herbicide antidotes. The key structures were confirmed by X-ray diffraction and 2D NMR techniques.