Irina A. Pustolaikina

Selective control of amino- (L1) and imino- (L2) tautomeric forms of 2-amino-4-thiazolinone was achieved via precise pH regulation (pH 11 and 6.5, respectively) during hydrochloride precursor neutralization, as confirmed by ¹H and ¹³C NMR spectroscopy. Reaction of protonated ligand with cobalt(II) chloride and silver(I) nitrate yielded [Co(L1)2Cl2] and [Ag(L1)3NO3] complexes. X-ray diffraction, IR, and UV–Vis spectral analyses revealed a distorted tetrahedral geometry for [Co(L1)2Cl2] with monodentate endocyclic nitrogen coordination. In contrast, [Ag(L1)3NO3] adopted an irregular coordination environment via endocyclic nitrogen and carbonyl oxygen atoms, assembling into chains. In vitro antimicrobial assays against Gram-positive (S. aureus, B. subtilis), Gram-negative (E. coli, P. aeruginosa) bacteria, and Candida albicans demonstrated a clear structure–activity relationship: free L1 < [Co(L1)2Cl2] < [Ag(L1)3NO3]. Uncoordinated L1 showed low-to-moderate activity (MIC = 64–128 μg/mL), silver complexation significantly enhanced potency, displaying broad-spectrum efficacy (MIC = 4–8 μg/mL) comparable to reference drugs. Molecular docking simulations against key microbial targets (DNA gyrase, penicillin-binding proteins, and CYP51) corroborated experimental findings, revealing the strongest binding affinity for [Ag(L1)3NO3] (up to –8.8 kcal/mol against S. aureus DNA gyrase) stabilized by extensive hydrogen bonding, electrostatic, and hydrophobic interactions. These results highlight [Ag(L1)3NO3] as a promising lead candidate for novel antimicrobial agents.

Integrastatins and their biogenetic counterparts possess a rare heterotetracyclic framework containing an unprecedented [6/6/6/6]-tetracyclic skeleton and a central [3/3/1]-bicyclic ketal core with high pharmaceutical potential, particularly due to their potent anti-HIV-1 integrase activity. Despite their promising scaffolds, a systematic consolidation of their chemistry and biology has been entirely lacking, creating a critical gap between the complex architecture of these natural polyketides and the targeted design of drug-like inhibitors. Herein, we present the first comprehensive review of this field, systematically analyzing 42 peer-reviewed publications from 1999 to 2025 retrieved from the Scopus, Web of Science, PubMed, and PubChem databases. Structural analysis confirms that while these rigid, nonplanar V-shaped molecules comply with Lipinski’s Rule of Five as a baseline filter for drug-likeness, deeper ADMET profiling further highlights their high predicted human intestinal absorption (HIA) alongside a low risk of cardiotoxicity. Synthetically, we detail how the field has fundamentally evolved from an arduous 11-step sequence in 2003 to highly streamlined, atom-economical one-step protocols in 2008 and 2021, culminating in the 2025 total syntheses that successfully resolved long-standing structural misinterpretations of epicoccolide A and epicocconigrone A. Furthermore, a comparative assessment across eight critical synthetic parameters highlights the operational trade-offs between step efficiency, scalability, and functional group tolerance in current cascade cyclizations. Biologically, we evaluate the extensive in vitro and in silico profiling of over 30 synthetic derivatives, highlighting their antimicrobial (M. bovis, S. aureus, P. carotovorum, C. albicans), antitubercular, and antiviral (SARS-CoV-2 and HIV-1 integrase inhibition) potencies. Integrating pharmacophore mapping with in silico ADMET profiling demonstrates that despite favorable absorption and cardiac safety, predicted liabilities such as human hepatotoxicity, carcinogenicity, and skin sensitization highlight critical areas for targeted structural modification. Ultimately, by bridging synthetic methodology with in silico and experimental bioactivity evaluation, this review establishes epoxybenzooxocine-based heterocycles as viable early-stage lead platforms and outlines strategic directions to advance these scaffolds in targeted drug discovery.

Herein, we report an unexpected pseudo-multicomponent transformation discovered during attempts to selectively nitrate the pyridine core of 3-acetyl-2,4,6-trimethylpyridine (3). Despite employing standard nitration conditions, including KNO₃–H₂SO₄ and HNO₃–H₂SO₄ mixtures, electrophilic substitution of the aromatic ring did not occur. Instead, the reaction sequence promoted an in situ nitrozation, dehydration to nitrile oxide intermediates, and subsequent [3+2]-cycloaddition involving two substrate molecules. This process yielded a novel, highly functionalized furoxan derivative, precisely identified as 3,4-bis(2,4,6-trimethylnicotinoyl)-1,2,5-oxadiazole 2-oxide (5). The molecular architecture of compound 5 was established by ¹H and ¹³C NMR spectroscopy, mass spectrometry, elemental analysis, and single-crystal X-ray diffraction (XRD) analysis. To elucidate the stereochemical and electronic features governing compound 5, DFT calculations were performed at the ωB97X-D/6-311++G(d,p) level of theory. The experimental crystallographic disorder of the N-oxide oxygen atom was computationally rationalized by the thermodynamic near-degeneracy (ΔG < 0.63 kcal/mol) of two orientational isomers (5a and 5b). Furthermore, frontier molecular orbital analysis within the framework of perturbation theory accounted for the head-to-tail regioselectivity during cyclization, while wide energy gaps (ΔE = 8.13–8.27 eV) and high chemical hardness (η = 4.07–4.14 eV) underscored the kinetic stability of the heterocycle. Phenotypic and target-specific in silico profiling using PASS Online identified Matrix Metalloproteinase-9 (MMP-9) as a relevant target for potential hemorheological and cardioprotective applications. Validated molecular docking simulations across three human MMP-9 crystallographic domains (PDB: 8K5Y, 6ESM, 4XCT) demonstrated competitive binding affinities and balanced Ligand Efficiency metrics (LE = 0.26–0.29 kcal/mol/heavy atom), anchoring compound 5 within the catalytic pocket via conventional hydrogen bonds and π-mediated interactions. Finally, in vitro evaluations using a blood hyperviscosity model confirmed significant hemorheological efficacy, as compound 5 effectively prevented the rise in blood viscosity, outperforming the reference drug pentoxifylline. The convergence of computational insights and experimental functional activity establishes this novel bis(nicotinoyl)furoxan framework as a promising candidate for further hemorheological and cardioprotective applications.

The paper presents the synthesis of new naphthyl-containing derivatives of thiosemicarbazide and thiourea, their water-soluble inclusion complexes with β-cyclodextrin, as well as an assessment of their potential antiviral and hemorheological activity. As a criterion for the specific antiviral effect of new compounds, their chemotherapeutic indices were calculated using predictive analytics tools driven by artificial intelligence and molecular docking methods. Molecular docking studies with three protein targets PknB (2FUM), DprE1 (6HEZ), and InhA (1ENY) confirmed strong and specific ligand–protein interactions. The effects of structural features of new compounds on the rheological characteristics of blood were considered, and the most promising samples were identified for further in-depth in vitro study of their specific biological activity. The performed thermoanalytical study showed that the structure of the included ligand, as well as the shape of the receptor, significantly affect the thermal stability and kinetic parameters of the decomposition of the inclusion complex. In silico evaluation of the newly synthesized compounds revealed promising biological activity profiles, with all compounds demonstrating predicted antimycobacterial and antituberculosis potential. In silico analysis of the newly synthesized compounds revealed favorable biological activity profiles, with all candidates demonstrating predicted antimycobacterial and antituberculosis potential.

Terpyridines are well-known ligands in coordination chemistry, are valued for their conformational flexibility and strong metal-binding properties, and are also of interest as fluorophores. This study focused on the synthesis and comprehensive investigation of a new class of bis-oxazolo[5,4-b]pyridine derivatives, designed based on their structural similarity to terpyridines. Four novel compounds, 4a–d, were synthesized by cyclization of amide derivatives of 3-aminopyridin-2(1H)-ones using pyridine-2,6-dicarboxylic acid and its dichloride as key acidic components. Their structures and purity were confirmed by melting point analysis, high-resolution mass spectrometry, and ¹H, ¹³C NMR spectroscopy. Compounds 4a–c exhibit UV absorption at 323–357 nm and intense blue to deep-blue fluorescence (357–474 nm, цi ≈ 0.32–0.84) in chloroform, dichloromethane, and acetonitrile, attributed to p–p* transitions within the conjugated ring system. These findings suggest their potential as phosphors for organic electronics. Computational modeling of 4a–c molecules provided insight into their electronic structures, conformational stability, and predicted optical behavior. The most stable conformers (4a–II, 4b–II, 4c–II′) exhibited a progressive decrease in the HOMO–LUMO gap from 4a to 4c, correlated with the enhancement of photoactivity. Among them, compound 4a stands out as the most promising luminophore, displaying the most intense and narrow luminescence band, owing to its high molecular symmetry and stable emission characteristics. Overall, this study lays the foundation for future studies of bis(oxazolo[5,4-b]pyridine) derivatives in coordination chemistry and optoelectronic materials development.

Terpyridines are well-known ligands in coordination chemistry due to their conforma-tional flexibility and strong metal-binding properties; therefore, they serve as attractive platforms for the design and synthesis of new functional derivatives. This study focused on the synthesis and comprehensive investigation of a new class of bis-oxazolo[5,4-b]pyridine derivatives, designed based on their structural similarity to terpyridines. Four novel compounds 4a–d were synthesized by cyclization of amide de-rivatives of 3-aminopyridin-2(1H)-ones using pyridine-2,6-dicarboxylic acid and its di-chloride as key acidic components. Their structures and purity were confirmed by melt-ing point analysis, high-resolution mass spectrometry, and detailed 1H NMR spectros-copy. Photophysical studies in chloroform, dichloromethane, and acetonitrile revealed that compounds 4a–c exhibit intense blue to deep blue fluorescence (л_max 323–347 nm) with high quantum yields (φi ≈ 0.32–0.84), attributed to р–π* transitions within the con-jugated ring system. These findings suggest their potential as air-stable phosphors for organic electronics. Computational modeling of 4a–c molecules provided insight into their electronic structures, conformational stability, and predicted optical behavior. The most stable conformers (4a–II, 4b–II, 4c–II′) showed decreasing HOMO–LUMO gaps and photoactivity from 4a to 4c, with 4a–II emerging as the most promising fluorophore due to its high symmetry and consistent emission. Overall, this study lays the foundation for future studies of bis(oxazolo[5,4-b]pyridine) derivatives in coordination chemistry and optoelectronic materials development.

Chelate complexes of copper(II) are widely used today in various sectors of the national economy, including medicine and pharmacology, biotechnology and agriculture, catalysis, and materials science. Pyridyl-containing β-diketones possess unique properties and can act as chelating ligands for metals, making them promising candidates for the development of metal-based pharmaceutical compounds. Therefore, the development and discovery of new copper(II) chelate complexes are of great interest and practical significance. In this work, new copper(II) chelate complexes of pyridyl-containing beta-diketonates were synthesized for the first time. Complexation between pyridyl-containing β-diketones and copper(II) acetate with molar ratio 2:1 was carried out in ethanol at a temperature not exceeding 50 ºC for 1 hour, with the yield of products IIIa–d ranging from 8.5 % to 31.3 %. The synthesized complexes were characterized using IR spectroscopy, atomic emission spectroscopy, and mass spectrometry, as well as DFT calculations, PASS prediction, and molecular docking. It was shown that all synthesized chelates exhibit biological activity as nicotinic receptor antagonists, with Pa values ranging from 0.821 to 0.915, and as dehydro-L-gulonate decarboxylase inhibitors, with Pa values exceeding 0.75. Molecular docking simulations with the alpha2 nicotinic acetylcholine receptor (PDB ID: 5FJV) confirmed high potential of synthesized chelates as nicotinic receptor antagonists and they can be recommended for further evaluation of therapeutic relevance through in vitro and in vivo studies.

The paper presents the results of a study on the preparation of water - soluble complexes of inclusions of 4 - and 2 - hydroxyhydrazides of benzoic acid and their hydrazones with cyclodextrins (β - CD, γ - CD) in an aqueous alcohol solution. Methods. The complexat ion of the obtained hydrazones with -  - ,  - ,  - cyclodextrins was studied in silico using molecular docking and modeling methods. Results and discussion. All the investigated hydrazones demonstrated the best value of binding affinity with β - cyclodextrin. The efficiency o f binding of the studied hydrazones to cyclodectrins is provided pr imarily by the correspondence of the geometric parameters of the "guest" and "host" molecules, as well as the formation of intermolecular hydrogen bonds. The complexation of the studied c γ - CD hydrazones proceeds with the participation of both internal pro tons of the cyclodextrin cavity and those located on the outer surface of the conical cone to form mixed supramolecular complexes. The spectral and thermochemical properties of the inclusion complexes were characterized using IR, 1 H, and 13 C NMR spectrosco py. Conclusion. The optimal conditions proposed in the work for the encapsulation of hydrazone derivatives of benzoic acid can be used in the preparation of water - soluble forms of similar compounds.

Integrastatins are naturally occurring heterotetracyclic compounds with a broad spectrum of biological activity. A number of new structural analogues of integrastatins 2a-u have been synthesized using a novel one-step method [1], but a systematic theoretical study of their structural features and biological activity has not been realized. This study aimed to in silico investigate physicochemical and bioactivity properties for a series of 21 new synthetic analogues of natural integrastatins. Global chemical reactivity descriptors was assessed using DFT B3LYP 6-311++G(d, p) CPCM (solvent — water) calculations. High ionization potential IP in the range from 5.9 to 7.1 eV and electron affinity EA at the level of 2.1 to 3.2 eV were shown, which together with a sufficiently large energy gap DEgap from 3.8 to 4.6 eV indicates the hard nature of the compounds 2a-u. Antiviral activity and inhibitory potential as CYP2C19 inducers were identified using the PASSOnline resource. According to the results of molecular docking studies Human immunodeficiency virus HIV-1 reverse transcriptase protein (PDB ID: 3V81) and protein of the RNA-dependent RNA polymerase of the SARS-CoV-2 (PDB ID: 7AAP) can serve as a likely biological target for the compounds 2a-u. Potentially high oral efficacy and a promising safety profile for the therapeutic use were showed using ADMETlab 3.0 online portal. Further experimental in vitro and in vivo studies of the pharmaceutical potential of compounds 2a-u is need for more accurate evaluation the assumptions made on the basis of in silico approach.