Search Results (24)

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. Full article

Functionalized nitrile oxides have attracted increasing attention because the incorporated functional groups not only influence cycloaddition reactivity but also provide valuable handles for subsequent molecular diversification. Despite their considerable synthetic potential, however, the development of practical methods for generating functionalized nitrile oxides has remained challenging because suitable precursors are often difficult to access and many functional groups are incompatible with conventional generation conditions. Consequently, only a limited number of reliable precursor systems have been established. This review summarizes recent advances in the generation of nitrile oxides bearing synthetically valuable acyl, ester, amide, and cyano functionalities, together with the development of synthetic equivalents that circumvent the intrinsic instability of these reactive intermediates. Particular emphasis is placed on 2-methyl-4-nitroisoxazoline-5(2H)-one (MeIOx), which serves as a practical precursor to (N-methylcarbamoyl)nitrile oxide. Remarkably, this nitrile oxide is generated simply by treatment with water under neutral conditions and undergoes efficient 1,3-dipolar cycloaddition with alkenes, alkynes, nitriles, and 1,3-dicarbonyl compounds to afford structurally diverse isoxazol(in)e and 1,2,4-oxadiazole derivatives. Furthermore, post-cycloaddition transformation of the N-methylcarbamoyl group into carboxyl, ester, amide, acyl, and formyl functionalities enables MeIOx to function as a practical synthetic equivalent of a broad range of functionalized nitrile oxides. The review also highlights the unique chemistry of the pyridinium salt PyIOx, whose ring-opening reaction provides cyano-aci-nitroacetate as a synthetic equivalent of the highly unstable (cyano)nitrile oxide. These complementary strategies significantly expand the scope of nitrile oxide chemistry and establish practical platforms for the synthesis of highly functionalized heterocycles. Full article

A series of novel fluorescent donor–acceptor–donor (D-A-D) dyes containing [1,2,5]oxadiazolo[3,4-d]pyridazine and its 1-oxide as electron-withdrawing groups has been synthesized and thoroughly investigated using X-ray diffraction and molecular spectroscopy methods. This study showed that the introduction of N-oxide into the 1,2,5-oxadiazole ring in the acceptor fragment leads to a significant decrease in the luminescence intensity and quantum yield of the dyes. A comprehensive comparison of the photophysical properties of the obtained compounds containing the 1,2,5-oxadiazole ring with the previously studied [1,2,5]thia- and 1,2,5-selenadiazolo[3,4-d]pyridazine analogs showed that the oxygen substitution in the acceptor fragment shifts the phosphorescence maximum from the NIR region of 980–1100 nm to the red region of 690–770 nm. In contrast, for oxygen- and sulfur-containing dyes, purely red fluorescence with a maximum in the spectral range of 620–900 nm is observed. The crystal structures of furoxan-containing 3d·½CHCl₃ and furazan-containing 4d exhibit a non-planar [1,2,5]oxadiazolo[3,4-d]pyridazine fragment. We have found that short non-covalent interactions of the furoxan system with a lattice chloroform molecule in 3d lead to luminescence quenching. Meanwhile, in the 4d dye, the intermolecular π-π interactions of pyridazine nitrogen atoms with the N-carbazolyl group of the adjacent molecule should facilitate intermolecular charge transfer (ICT) emission. Thus, the luminescence maxima for these dyes can be tuned across a broad range of 700–1100 nm by varying the number of chalcogen atoms, highlighting the potential for tailoring optical properties in optoelectronic applications. Full article

Background/Objectives: Oxidative stress, the Warburg effect, and resistance to apoptosis are key hallmarks driving colorectal tumorigenesis. This study aimed to develop novel multi-target compounds capable of modulating these pathways. Methods: A library of 24 newly synthesized compounds—incorporating annulated thiophene, thiazole, quinazolinone, 2-oxoindoline, and 1,2,3-oxadiazole scaffolds, as well as N-(1-(4-hydroxy-3-methoxyphenyl)-3-oxo-3-(2-(phenylcarbamothioyl)hydrazineyl) prop-1-en-2-yl)benzamide—was evaluated for antioxidant activity (DPPH assay), PDK-1 and LDHA inhibition, cytotoxic effects against LoVo and HCT-116 colon carcinoma cells, with parallel assessment of safety profiles on normal HUVECs. The underlying anticancer mechanism of the most active compound was investigated through analysis of cell cycle distribution, apoptosis induction, intracellular reactive oxygen species levels, mitochondrial membrane potential disruption, and expression levels of apoptosis-related genes. Molecular docking assessed binding interactions within LDHA and PDK-1 active sites. The physicochemical, drug-likeness, and ADMET properties of the multi-bioactive candidates were predicted in silico. Results: Among the synthesized compounds, thiophenes 3b and 3d exhibited potent PDK-1/LDHA and DPPH/LDHA inhibitions, along with significant cytotoxic effects on LoVo/HCT-116 cells (IC₅₀ in µM: 190.30/170.21 and 156.60/160.96, respectively), while showing minimal cytotoxicity toward HUVECs. Molecular docking revealed favorable interactions with key amino acid residues within the LDHA and/or PDK-1 active sites. Compound 3d notably induced G2/M (LoVo) and G1 (HCT-116) arrest and promoted apoptosis via enhancing ROS generation, modulating Bax/Bcl-2 expressions, disrupting mitochondrial membrane potential, and ultimately activating caspses-3. In silico predictions indicated their promising drug-likeness and pharmacokinetics, though high lipophilicity, poor solubility (especially for 3b), and potential toxicity risks were identified as limitations. Conclusions: Thiophenes 3b and 3d emerged as promising multi-target candidates; however, structural optimization is warranted to enhance their solubility, bioavailability, and safety to support further development as lead anti-colon cancer agents. Full article

An unparalleled copper(I)-catalyzed synthesis of 1,3,4-oxadiazoles from tertiary amines in one step has been described. The one-pot reactions involving (N-isocyanimine)triphenylphosphorane, tertiary amines, and carboxylic acids resulted in the formation of 1,3,4-oxadiazoles in moderate to good yields through a consecutive oxidative Ugi/aza-Wittig reaction, enabling the direct functionalization of sp³ C-H bonds adjacent to the nitrogen atom. This method offered several notable advantages, including ligands-free, exceptional productivity and a high functional group tolerance. The preliminary biological evaluation demonstrated that compound 4f inhibited hepatoma cells efficiently, suggesting potentially broad applications of the approach for synthesis and medicinal chemistry. Full article

Three new compounds based on the combination of furoxan (1,2,5-oxadiazole N-oxide) and oxa-[5,5]bicyclic ring were synthesized. Among them, the nitro compound showed satisfactory detonation properties (Dv, 8565 m s⁻¹; P, 31.9 GPa), which is comparable to the performance of RDX (a classic high-energy secondary explosive). Additionally, the introduction of the N-oxide moiety and oxidation of the amino group more effectively improved the oxygen balance and density (d, 1.81 g cm⁻³; OB%, +2.8%) of the compounds compared to furazan analogues. Combined with good density and oxygen balance as well as moderate sensitivity, this type of furoxan and oxa-[5,5]bicyclic structure will open up a platform for the synthesis and design of new high-energy materials. Full article

In this research, six novel unsymmetrical imino-1,8-naphthalimides (AzNI) were synthesized. Comprehensive thermal (thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC), optical (UV-Vis, photoluminescence), and electrochemical (CV, DPV) studies were carried out to characterize these new compounds. The molecules showed the onset of thermal decomposition in the temperature range 283–372 °C and molecular glass behavior. Imino-1,8-naphthalimides underwent reduction and oxidation processes with the electrochemical energy band gap (E_g) below 2.41 eV. The optical properties were evaluated in solvents with different polarities and in the solid-state as a thin films and binary blends with poly(N-vinylcarbazole): (2-tert-butylphenyl-5-biphenyl-1,3,4-oxadiazole) (PVK:PBD). Presented compounds emitted blue light in the solutions and in the green or violet spectral range in the solid-state. Their ability to emit light under external voltage was examined. The devices with guest-host structure emitted light with the maximum located in the blue to red spectral range of the electroluminescence band (EL) depending on the content of the AzNI in the PVK:PBD matrix (guest-host structure). Full article

Due to the introduction of oxygen atoms, N-oxide energetic compounds have a unique oxygen balance, excellent detonation properties, and a high energy density, attracting the extensive attention of researchers all over the world. N-oxides are classified into two categories based on the structural characteristics of their skeletons: azine N-oxides and azole N-oxides, whose N→O coordination bonds are formed during cyclization. There are six kinds of azine N-oxides, namely 1,2,3,4-tetrazine-1,3-dioxide, 1,2,3,5-tetrazine-2-oxide, 1,2,3-triazine-3-oxide, 1,2,3-triazine-2-oxide, pyridazine-1,2-dioxide, and pyrazine-1-oxide. Azole N-oxides include 1,2,5-oxadiazole-2-oxide, pyrazole-1-oxide, and triazole-1-oxide. Synthetic strategies towards these two categories of N-oxides are fully reviewed. Corresponding reaction mechanisms towards the aromatic N-oxide frameworks and examples that use the frameworks to create high-energy substances are discussed. Moreover, the energetic properties of N-oxide energetic compounds are compared and summarized. Full article

1,2,4-Oxadiazole is a heterocycle with wide reactivity and many useful applications. The reactive O-N bond is usually reduced using molecular hydrogen to obtain amidine derivatives. NH₄CO₂H-Pd/C is here demonstrated as a new system for the O-N reduction, allowing us to obtain differently substituted acylamidine, acylguanidine and diacylguanidine derivatives. The proposed system is also effective for the achievement of a reductive rearrangement of 5-(2′-aminophenyl)-1,2,4-oxadiazoles into 1-alkylquinazolin-4(1H)-ones. The alkaloid glycosine was also obtained with this method. The obtained compounds were preliminarily tested for their biological activity in terms of their cytotoxicity, induced oxidative stress, α-glucosidase and DPP4 inhibition, showing potential application as anti-diabetics. Full article

An Se-derivative of amidoxime was synthesized for the first time as a result of the reaction of oxidative polycondensation of N’-hydroxy-1,2,5-oxadiazole-3-carboximidamide with SeO₂: its elementary units are linked to each other due to the formation of strong diselenide bridges. The element composition of the material was established, and the structure of the elementary unit was suggested. The sorption-selective properties were evaluated, and it was found that the adsorbent can be used for the selective recovery of U (VI) from liquid media with a pH of 6–9. The effect of some anions and cations on the efficiency of recovery of U (VI) was estimated. Composite materials were fabricated, in which silica gel with a content of 35, 50, and 65 wt.% was used as a matrix to be applied in sorption columns. The maximum values of adsorption of U (VI) calculated using the Langmuir equation were 620–760 mg g⁻¹ and 370 mg g⁻¹ for the composite and non-composite adsorbents, respectively. The increase in the kinetic parameters of adsorption in comparison with those of the non-porous material was revealed, along with the increase in the specific surface area of the composite adsorbents. In particular, the maximum sorption capacity and the rate of absorption of uranium from the solution increased two-fold. Full article

A new series of 1,8-naphtalimides containing an imine bond at the 3-position of the naphthalene ring was synthesized using ¹H, ¹³C NMR, FTIR, and elementary analysis. The impact of the substituent in the imine linkage on the selected properties and bioimaging of the synthesized compounds was studied. They showed a melting temperature in the range of 120–164 °C and underwent thermal decomposition above 280 °C. Based on cyclic and differential pulse voltammetry, the electrochemical behavior of 1,8-naphtalimide derivatives was evaluated. The electrochemical reduction and oxidation processes were observed. The compounds were characterized by a low energy band gap (below 2.60 eV). Their photoluminescence activities were investigated in solution considering the solvent effect, in the aggregated and thin film, and a mixture of poly(N-vinylcarbazole) (PVK) and 2-tert-butylphenyl-5-biphenyl-1,3,4-oxadiazole (PBD) (50:50 wt.%). They demonstrated low emissions due to photoinduced electron transport (PET) occurring in the solution and aggregation, which caused photoluminescence quenching. Some of them exhibited light emission as thin films. They emitted light in the range of 495 to 535 nm, with photoluminescence quantum yield at 4%. Despite the significant overlapping of its absorption range with emission of the PVK:PBD, incomplete Förster energy transfer from the matrix to the luminophore was found. Moreover, its luminescence ability induced by external voltage was tested in the diode with guest–host configuration. The possibility of compound hydrolysis due to the presence of the imine bond was also discussed, which could be of importance in biological studies that evaluate 3-imino-1,8-naphatalimides as imaging tools and fluorescent materials for diagnostic applications and molecular bioimaging. Full article

Starting from indomethacin (IND), one of the most prescribed non-steroidal anti-inflammatory drugs (NSAIDs), new nitric oxide-releasing indomethacin derivatives with 1,3,4-oxadiazole-2-thiol scaffold (NO-IND-OXDs, 8a–p) have been developed as a safer and more efficient multitarget therapeutic strategy. The successful synthesis of designed compounds (intermediaries and finals) was proved by complete spectroscopic analyses. In order to study the in silico interaction of NO-IND-OXDs with cyclooxygenase isoenzymes, a molecular docking study, using AutoDock 4.2.6 software, was performed. Moreover, their biological characterization, based on in vitro assays, in terms of thermal denaturation of serum proteins, antioxidant effects and the NO releasing capacity, was also performed. Based on docking results, 8k, 8l and 8m proved to be the best interaction for the COX-2 (cyclooxygense-2) target site, with an improved docking score compared with celecoxib. Referring to the thermal denaturation of serum proteins and antioxidant effects, all the tested compounds were more active than IND and aspirin, used as references. In addition, the compounds 8c, 8h, 8i, 8m, 8n and 8o showed increased capacity to release NO, which means they are safer in terms of gastrointestinal side effects. Full article

Coumarin and coumarin derivatives are bioactive compounds that have an important role in medicinal chemistry, for example in the development of anti-inflammatory, anticancer and antiviral drugs. These compounds are also very powerful antioxidants that successfully scavenge free radicals and prevent or alleviate oxidative stress. The antioxidant potential of selected heterocyclic compounds containing coumarin core was investigated theoretically, the focus of this study was on hydrogen atom transfer mechanism (HAT) and single electron transfer followed by a proton transfer mechanism (SET-PT). Using MOPAC2012 PM7, reaction enthalpies related to the cleavage of O–H, N–H and C–H bonds via selected mechanisms of free radical scavenging were studied and calculated. The effect of the position of the hydroxyl group, as well as other functional groups, on the antioxidant activity, was examined. Based on obtained results, Schiff bases, thiosemicarbazides, oxadiazoles and 4-thiazolidinones containing one or more OH– groups exhibit higher radical scavenging properties. Full article

This work reports our first results in the area of the reactivity of coordinated chloroximes. The 1:2:2:2 Zn(NO₃)₂∙6H₂O/Eu(NO₃)₃∙6H₂O/ClpaoH/Et₃N reaction mixture in MeOH, where ClpaoH is pyridine-2-chloroxime, resulted in complex [ZnCl₂(L)] (1); L is the di(2-pyridyl)furoxan [3,4-di(2-pyridyl)-1,2,5-oxadiazole-2-oxide] ligand. The same complex can be isolated in the absence of the lanthanoid. The direct reaction of ZnCl₂ and pre-synthesized L in MeOH also provides access to 1. In the tetrahedral complex, L behaves as a N_pyridyl,N′_pyridyl-bidentate ligand, forming an unusual seven-membered chelating ring. The Hirshfeld Surface analysis of the crystal structure reveals a multitude of intermolecular interactions, which generate an interesting 3D architecture. The complex has been characterized by FTIR and Raman spectroscopies. The structure of 1 is not retained in DMSO (dimethylsulfoxide) solution, as proven by NMR (¹H, ¹³C, ¹⁵N) spectroscopy and its molar conductivity value. Upon excitation at 375 nm, solid 1 emits blue light with a maximum at 452 nm; the emission is of an intraligand character. The geometric and energetic profiles of possible pathways involved in the reaction of ClpaoH and Zn(NO₃)₂∙6H₂O in MeOH in the presence of Et₃N has been investigated by DFT (Density Functional Theory) computational methodologies at the PBE0/Def2-TZVP(Cr)∪6-31G(d,p)(E)/Polarizable Continuum Model (PCM) level of theory. This study reveals an unprecedented cross-coupling reaction between two coordinated 2-pyridyl nitrile oxide ligands. Full article

The manuscript describes the synthesis of new racemic and chiral linked paracyclophane assigned as N-5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)carbamoyl)-5’-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)carboxamide. The procedure depends upon the reaction of 5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)hydrazide with 5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)isocyanate. To prepare the homochiral linked paracyclophane of a compound, the enantioselectivity of 5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)carbaldehyde (enantiomeric purity 60% ee), was oxidized to the corresponding acid, which on chlorination, gave the corresponding acid chloride of [2.2]paracyclophane. Following up on the same procedure applied for the preparation of racemic-carbamoyl and purified by HPLC purification, we succeeded to obtain the target Sp-Sp-N-5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)carbamoyl)-5’-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)carboxamide. Subjecting N-5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)hydrazide to various isothiocyanates, the corresponding paracyclophanyl-acylthiosemicarbazides were obtained. The latter compounds were then cyclized to a new series of 5-(1,4(1,4)-dibenzenacyclohexaphane-1²-yl)-2,4-dihydro-3H-1,2,4-triazol-3-thiones. 5-(1,4(1,4)-Dibenzenacyclohexaphane-1²-yl)-1,3,4-oxadiazol-2-amines were also synthesized in good yields via internal cyclization of the same paracyclophanyl-acylthiosemicarbazides. NMR, IR, and mass spectra (HRMS) were used to elucidate the structure of the obtained products. The X-ray structure analysis was also used as an unambiguous tool to elucidate the structure of the products. Full article