Eva S. Daus

The paper presents an effective method for synthesizing new 3-amino-4-aryl-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridines via tandem S-alkylation and Thorpe–Ziegler heterocyclization. The initial reagents were 4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates of morpholinium (or N-methylmorpholinium). Their reaction with α-halocarbonyl compounds in excess alcoholic KOH gave target products in 59–78% yields. Structures were confirmed by IR, NMR, and elemental analysis; the C4 chiral configuration was established. In-silico analysis showed the compounds meet Lipinski’s “rule of five”, with predicted high gastrointestinal absorption and blood–brain barrier penetration; toxicological assessment gave mixed results. Biological testing on sunflower seedlings revealed some derivatives have a pronounced antidote effect against the herbicide 2,4-D, assessed via increased hypocotyl and root lengths. The synthetic approach thus yields heterocyclic compounds promising as plant protectors in agrochemistry, warranting further study of their activity and mechanisms.

The aim of this work was to synthesize previously unknown thieno[2,3-b]pyridines bearing a β-ketoamide moiety, to study their structure, and to evaluate their agrochemical potential as 2,4-D herbicide safeners. A series of 3-(3-aminothieno[2,3-b]pyridine-2-yl)-3-oxo-N-phenylpropanamides were prepared via S-alkylation of readily available 2-thioxonicotinonitriles or 3-cyanopyridine-2-thiolates with γ-bromoacetoacetanilide, followed by base-promoted Thorpe–Ziegler cyclization. The structure of 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide was unambiguously established by single-crystal X-ray diffraction. Quantum chemical calculations (B3LYP-D3BJ/6-311+G(2d,p)) revealed that the ketone form is significantly more stable than the enol tautomer with a calculated equilibrium constant in DMSO of 1.52 × 10⁻⁵, which is consistent with the absence of enol form signals in the NMR spectra. The calculated IR frequencies, after scaling, showed excellent agreement with experimental data. Additionally, we found that 4-[(3-cyano-4,6-dimethylpyridin-2-yl)thio]-3-oxo-N-phenylbutanamide undergoes intramolecular cyclization upon heating in AcOH or DMF, to give 4-hydroxy-7,9-dimethylthieno [2,3-b:4,5-b′]dipyridin-2(1H)-one via aniline elimination, thus providing an alternative route to tricyclic thieno [2,3-b;4,5-b]dipyridine ensembles. Agrochemical screening demonstrated that some compounds exhibit pronounced antidote activity against the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) in sunflower seedlings, with root and hypocotyl protection reaching 119–156% in laboratory tests. Field trials for the three most active compounds confirmed their efficacy, providing crop yield increases of 46–57% relative to the herbicide-only control. These results indicate that the newly synthesized thienopyridine β-ketoamides represent a promising class of 2,4-D herbicide safeners.

A series of previously undescribed 3-amino-4,5,6,7-tetrahydrothieno[2,3- b ]pyridines was prepared in 44–79% yields through alkylation of N -methylmorpholinium 3-cyano-4-(4-methoxyphenyl)-6-oxo-1,4,5,6-tetrahydropyridine-2-thiolate followed by Thorpe–Ziegler cyclization in the presence of KOH. An in silico predictor analysis was conducted to determine the bioavailability parameters and potential protein targets for the new compounds. Under laboratory experimental conditions on sunflower seedlings, some of the synthesized compounds demonstrated a moderate antidote effect against the herbicide 2,4-D.

Morpholinium (N-methylmorpholinium) 4-aryl-6-oxo-3-cyano-1,4,5,6-tetrahydropyridine-2-thiolates obtained by the reaction of cyanothioacetamide and aromatic aldehydes with Meldrum’s acid in the presence of a base undergo a tandem S-alkylation–Thorpe–Ziegler heterocyclization reaction upon treatment with α-halo carbonyl compounds in the presence of excess KOH. Predictive in silico analysis and molecular docking were performed for the newly synthesized 3-amino-4-aryl-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridines to identify bioavailability parameters and potential protein targets. In laboratory experiments on sunflower seedlings, some of the compounds exhibited a pronounced safening effect against the herbicide 2,4-D (2,4-dichlorophenoxyacetic acid).

This work aimed to synthesize new derivatives of 2-hydrazinylpyridine-3-carbonitrile and to investigate their biological activity as safeners for the 2,4-D herbicide. The new 2-hydrazinylnicotinonitriles were obtained in high yields (up to quantitative) under mild conditions (25 °C, dioxane) by treating 4,6-diaryl-2-bromo-3-cyanopyridines with hydrazine hydrate. The latter were synthesized by brominating 2-(3-oxo-1,3-diarylpropyl)malononitriles, the Michael adducts, which are readily available from 1,3-diarylpropenones (chalcones) and malononitrile. An unusual side product of the bromination/carbocyclization was isolated and characterized; it consisted of co-crystals of 3-benzoyl-4-hydroxy-4-phenyl-2,6-di-(p-tolyl)cyclohexane-1,1-dicarbonitrile and 3-benzoyl-5-bromo-4-hydroxy-4-phenyl-2,6-di-(p-tolyl)cyclohexane-1,1-dicarbonitrile at a ~4:6 ratio. The new 2-hydrazinylnicotinonitriles react with halogen-containing aromatic aldehydes to form the corresponding hydrazones. The biological activity of the new nicotinonitriles was examined for their function as 2,4-D antidotes. It was found that, under laboratory conditions, eight of the synthesized compounds exhibited a notable antidote effect against 2,4-D on sunflower seedlings.

The aim of this work was to prepare new heterodimeric molecules containing pharmacophoric fragments of 3-cyanoquinoline/3-aminothieno[2,3-b]pyridine/3-aminothieno[2,3-b]quinoline on one side and phenothiazine on the other. The products were synthesized via selective S-alkylation of readily available 2-thioxo-3-cyanopyridines or -quinolines with N-(chloroacetyl)phenothiazines, followed by base-promoted Thorpe–Ziegler isomerization of the resulting N-[(3-cyanopyridin-2-ylthio)acetyl]phenothiazines. We found that both the S-alkylation and the Thorpe–Ziegler cyclization reactions, when conducted with KOH under heating, were accompanied to a significant extent by a side reaction involving the elimination of phenothiazine. Optimization of the conditions (0–5 °C, anhydrous N,N-dimethylacetamide and NaH or t-BuONa as non-nucleophilic bases) minimized the side reaction and increased the yields of the target heterodimers. The structures of the products were confirmed by IR spectroscopy, ¹H, and ¹³C DEPTQ NMR studies. It was demonstrated that the synthesized 3-aminothieno[2,3-b]pyridines can be acylated with chloroacetyl chloride in hot chloroform. The resulting chloroacetamide derivative reacts with potassium thiocyanate in DMF to form the corresponding 2-iminothiazolidin-4-one; in this process, phenothiazine elimination does not occur, and the Gruner–Gewald rearrangement product was not observed. The structural features and spectral characteristics of the synthesized 2-iminothiazolidin-4-one derivative were investigated by quantum chemical methods at the B3LYP-D4/def2-TZVP level. A range of drug-relevant properties was also evaluated using in silico methods, and ADMET parameters were calculated. A molecular docking study identified a number of potential protein targets for the new heterodimers, indicating the promise of these compounds for the development of novel antitumor agents.

The aim of this work was to prepare new heterodimeric molecules containing pharmacophoric fragments of 3-cyanoquinoline/3-aminothieno[2,3-b]pyridine/3-aminothieno[2,3- b]quinoline on one side, and phenothiazine – on the other. The products were synthesized via selective S-alkylation of readily available 2-thioxo-3-cyanopyridines or -quinolines with N-(chloroacetyl)phenothiazines, followed by base-promoted Thorpe-Ziegler isomerization of the resulting N-[(3-cyanopyridin-2-ylthio)acetyl]phenothiazines. We found that both the S-alkylation and the Thorpe-Ziegler cyclization reactions, when conducted with KOH under heating, were accompanied to a significant extent by a side reaction involving the elimination of phenothiazine. Optimization of the conditions (0…5 °C, anhydrous N,N-dimethylacetamide and NaH or t-BuONa as non-nucleophilic bases) minimized the side reaction and increased the yields of the target heterodimers. The structures of the products were confirmed by IR spectroscopy, 1H and 13C DEPTQ NMR studies. It was demonstrated that the synthesized 3-aminothieno[2,3-b]pyridines can be acylated with chloroacetyl chloride in hot chloroform. The resulting chloroacetamide derivative reacts with potassium thiocyanate in DMF to form the corresponding 2-iminothiazolidin-4-one; in this process, phenothiazine elimination does not occur and the Gewald rearrangement product was not observed. The structural features and spectral characteristics of the synthesized 2-iminothiazolidin-4-one derivative were investigated by quantum chemical methods at the B3LYP-D4/def2-TZVP level. A range of drug-relevant properties were also evaluated using in silico methods, and ADMET parameters were calculated. A molecular docking study identified a number of potential protein targets for the new heterodimers, indicating the promise of these compounds for the development of novel antitumor agents.