Alexander V. Bespalov

Pyrano[3,2-b]pyrans and indolin-2-ones (oxindole) are two well-established pharmacophore frameworks that independently underpin a broad range of biologically active compounds, including enzyme inhibitors, antioxidants, and antiproliferative agents. Molecular hybridization—the deliberate fusion of two pharmacophores into a single scaffold—has emerged as a powerful strategy in medicinal chemistry for achieving multitarget activity profiles. Herein we report the design and synthesis of novel heterodimeric compounds that incorporate both fragments linked through a thioether bridge, assembled via a concise multistep route. α-Thiocyanatoacetophenone, obtained by nucleophilic substitution of phenacyl bromide with potassium thiocyanate in ethanol (88–93% yield), was treated with isatin in the presence of triethylamine in ethyl acetate to furnish triethylammonium thiolate 1 in up to 86% yield. S-Alkylation of 1 with chlorokojic acid in DMF afforded heterodimer 2, containing intact indolin-2-one and kojic acid fragments. Compound 2 was engaged in a three-component domino condensation with aromatic aldehydes or isatin and malononitrile under basic conditions, proceeding via sequential Knoevenagel condensation and intramolecular Michael cyclization to give pyrano[3,2-b]pyran-indolin-2-one heterodimers 3. Preliminary molecular docking against the monomeric Aβ40 (PDB ID: 2LFM) and the fibrillar Aβ40 model (PDB ID: 2LMN) of the β-amyloid peptide Aβ40, as well as human serum albumin (HSA), identified promising candidates exhibiting high binding affinities simultaneously toward all three targets, with the most favorable predicted docking scores reaching −9.79 kcal/mol for the fibrillar Aβ40 model (2LMN). The results establish the pyrano[3,2-b]pyran-indolin-2-one scaffold as a promising multitarget candidate for Alzheimer’s disease therapy, warranting further medicinal chemistry investigation.

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.

The structure of various tautomeric forms of 3-oxo-4-thiocyanato-N-phenylbutanamide (γ-thiocyanatoacetoacetanilide) has been studied in detail and their stability has been assessed using NMR spectroscopy, X-ray analysis, and quantum-chemical calculations. The reactions of this compound with some C- and N-nucleophiles have been investigated, and the structure and tautomerism of the products are discussed. Contrary to literature data, the azo coupling reaction of γ-thiocyanatoacetoacetanilide with aryldiazonium salts leads to (Z)-2-[2-arylhydrazinylidene]-3-oxo-4-thiocyanato-N-phenylbutanamides, whose structure has been confirmed by single crystal X-ray analysis. The synthesized compounds were tested for antimicrobial activity, and one of the products exhibited moderate activity against S. enterica and S. aureus.

Triethylammonium (E)-2-oxo-1-(2-oxoindolin-3-ylidene)-2-phenylethane-1-thiolate, readily obtained from phenacyl thiocyanate and isatin, undergoes efficient S-alkylation with alkyl halides in refluxing DMF. When ethyl 4-chloroacetoacetate is employed, the reaction affords (E)-3-[2-oxo-1-{(2-oxopropyl)thio}-2-phenylethylidene]indolin-2-one via in situ Krapcho decarboxylation of the intermediate β-keto ester; the structure was confirmed by X-ray crystallography. Quantum chemical calculations (ωB97X-3c/CPCM) reveal that the (E)-isomer of the starting thiolate is thermodynamically favored by ~18 kJ/mol over the (Z)-form in EtOAc. In silico ADMET profiling and protein-ligand docking studies indicate favorable bioavailability parameters and potential interactions with targets such as stromelysin-1 (MMP-3), FABP4, and PPAR-γ, suggesting possible anti-inflammatory and antidiabetic applications. Under laboratory conditions, the starting thiolate exhibits significant protective (antidote) activity against the herbicide 2,4-D in sunflower seedlings, increasing hypocotyl and root lengths by up to 126 and 154%, respectively.

A zinc complex of chelidonic acid (4-oxo-4H-pyran-2,6-dicarboxylic acid) was obtained by reaction with zinc oxide under isothermal conditions. Its composition was confirmed by elemental and thermogravimetric analyses, and its molecular structure was characterized using NMR and IR spectroscopy. Single-crystal X-ray diffraction revealed that the complex crystallizes as a one-dimensional coordination polymer, [ZnChel(H₂O)₄]_n, in the triclinic space group P-1, featuring a distorted octahedral Zn(II) center coordinated by two chelidonate ligands and four water molecules. This six-coordinate arrangement contrasts with previously described tetra-coordinated Zn–chelidonate complexes. Quantum-chemical calculations and molecular dynamics simulations indicated that, in aqueous solution, Zn(II) preferentially forms a monodentate ZnChel(H₂O)₅ species, consistent with the solid-state coordination environment. The interaction of the complex with bovine serum albumin (BSA) was examined by fluorescence, UV–Vis absorption, and circular dichroism spectroscopy, revealing a mixed static–dynamic quenching mechanism, moderate binding affinity, and hydrogen-bonding/van der Waals contributions accompanied by alterations in BSA secondary structure. These results expand the structural chemistry of chelidonic acid and provide biophysical insight into the protein-binding behavior of zinc chelidonate, supporting its potential relevance as a zinc-based bioactive compound.

The article presents the results of a study on the catalytic activity in the water dissociation reaction and the chemical structure of oxidized graphene samples with various degrees of oxidation. The catalytic activity was investigated using asymmetric bipolar membranes with a homogeneous anion-exchange layer based on a copolymer of N,N-diallyl-N,N-dimethylammonium chloride and ethylmethacrylate. It was shown that graphene oxidized by the Hummers’ method significantly accelerates the water dissociation process due to the presence of carboxyl and phenolic groups in its chemical structure. Graphene reduced by sodium borohydride and graphene oxidized by sodium dichromate exhibited significantly lower catalytic activity (Ub = 2.9 V and 2.8 V, respectively, at 3.75 mA/cm²) than graphene oxidized by Hummers’ method (Ub = 0.39 V at 3.5 mA/cm²). Compared to the initial asymmetric bipolar membrane (Ub = 7.0 V at 3.75 mA/cm²), a more than two-fold decrease in the overvoltage of the bipolar region was observed. In the first case, this is attributed to the high electronic conductivity of the catalyst, and in the second case, to the residual content of carboxylic and phenolic groups. The chemical structure of the oxidized and reduced graphene samples was studied by IR spectroscopy and quantum chemical methods at the r2scan-3c level. The presence of hydroxyl, carboxyl, carbonyl, and epoxy groups in the structure of oxidized graphene was confirmed both experimentally and theoretically. It was also established that the Lerf-Klinowski model of oxidized graphene agrees best with the experimental data.

As a result of the reaction between 5-hydroxy-4-oxo-4H-pyran-2,6-dicarboxylic acid (meconic acid, poppy acid) and magnesium acetate, a complex with the composition C₂₈H₆₂Mg₃O₅₄ {[Mg(H₂O)₆]₃·(Mec^2–)₂(HMec^–)₂· 8H₂O} was synthesized. The composition of the complex was determined based on energy-dispersive X-ray spectroscopy and atomic absorption spectroscopy. The structure of the complex was studied using spectroscopic methods (NMR, IR spectroscopy) as well as X-ray diffraction analysis. Based on potentiometric titration data and quantum chemical calculations, a possible composition of the magnesium complex with meconic acid in an aqueous solution was proposed. In vivo experiments demonstrated that the oral administration of magnesium meconate over 30 days promotes the accumulation of Mg²⁺ in myocardial tissues and activates the antioxidant potential by enhancing the expression of a number of antioxidant defense system proteins, such as Gclc, NFE2L2, SOD2, and CAT.

6-Aminopyridine-3,5-dicarbonitriles and 3,6-diamino-5-cyanothieno[2,3-b]pyridines are well known as compounds with a broad spectrum of bioactivity. In particular, such thienopyridines are known as inhibitors of scrapie prion infection replication and accumulation, as well as selective inhibitors of malaria plasmodia kinase-3 with a pronounced antimalarial effect. To expand the range of such compounds, we studied the reaction of 3,6-diaminothieno[2,3-b]pyridine-5-carbonitriles with chloroacetyl chloride. The analysis of the Fukui indices showed that in these compounds the amino group at the C(3) atom is the most reactive. In fact, the reaction with ClCH₂C(O)Cl leads to the predicted product. Other reactions of thienopyridines as well as data on the biological activity of the products are discussed.