Exploring Intra- and Intermolecular Interactions in Selected N-Oxides—The Role of Hydrogen Bonds

Intra- and intermolecular interactions have been explored in selected N-oxide derivatives: 2-(N,N-dimethylamino-N-oxymethyl)-4,6-dimethylphenyl (1) and 5,5’-dibromo-3-diethylaminomethyl-2,2’-biphenol N-oxide (2). Both compounds possess intramolecular hydrogen bonding, which is classified as moderate in 1 and strong in 2, and resonance-assisted in both cases. Density Functional Theory (DFT) in its classical formulation as well as Time-Dependent extension (TD-DFT) were employed to study proton transfer phenomena. The simulations were performed in the gas phase and with implicit and explicit solvation models. The obtained structures of the studied N-oxides were compared with experimental data available. The proton reaction path was investigated using scan with an optimization method, and water molecule reorientation in the monohydrate of 1 was found upon the proton scan progress. It was found that spontaneous proton transfer phenomenon cannot occur in the electronic ground state of the compound 1. An opposite situation was noticed for the compound 2. The changes of nucleophilicity and electrophilicity upon the bridged proton migration were analyzed on the basis of Fukui functions in the case of 1. The interaction energy decomposition of dimers and microsolvation models was investigated using Symmetry-Adapted Perturbation Theory (SAPT). The simulations were performed in both phases to introduce polar environment influence on the interaction energies. The SAPT study showed rather minor role of induction in the formation of homodimers. However, it is worth noticing that the same induction term is responsible for the preference of water molecules’ interaction with N-oxide hydrogen bond acceptor atoms in the microsolvation study. The Natural Bond Orbital (NBO) analysis was performed for the complexes with water to investigate the charge flow upon the polar environment introduction. Finally, the TD-DFT was applied for isolated molecules as well as for microsolvation models showing that the presence of solvent affects excited states, especially when the N-oxide acceptor atom is microsolvated.     

Revealing Intra- and Intermolecular Interactions Determining Physico-Chemical Features of Selected Quinolone Carboxylic Acid Derivatives

The intra- and intermolecular interactions of selected quinolone carboxylic acid derivatives were studied in monomers, dimers and crystals. The investigated compounds are well-recognized as medicines or as bases for further studies in drug design. We employed density functional theory (DFT) in its classical formulation to develop gas-phase and solvent reaction field (PCM) models describing geometric, energetic and electronic structure parameters for monomers and dimers. The electronic structure was investigated based on the atoms in molecules (AIM) and natural bond orbital (NBO) theories. Special attention was devoted to the intramolecular hydrogen bonds (HB) present in the investigated compounds. The characterization of energy components was performed using symmetry-adapted perturbation theory (SAPT). Finally, the time-evolution methods of Car–Parrinello molecular dynamics (CPMD) and path integral molecular dynamics (PIMD) were employed to describe the hydrogen bond dynamics as well as the spectroscopic signatures. The vibrational features of the O-H stretching were studied using Fourier transformation of the autocorrelation function of atomic velocity. The inclusion of quantum nuclear effects provided an accurate depiction of the bridged proton delocalization. The CPMD and PIMD simulations were carried out in the gas and crystalline phases. It was found that the polar environment enhances the strength of the intramolecular hydrogen bonds. The SAPT analysis revealed that the dispersive forces are decisive factors in the intermolecular interactions. In the electronic ground state, the proton-transfer phenomena are not favourable. The CPMD results showed generally that the bridged proton is localized at the donor side, with possible proton-sharing events in the solid-phase simulation of stronger hydrogen bridges. However, the PIMD enabled the quantitative estimation of the quantum effects inclusion—the proton position was moved towards the bridge midpoint, but no qualitative changes were detected. It was found that the interatomic distance between the donor and acceptor atoms was shortened and that the bridged proton was strongly delocalized.     

Mesoscopic-and macroscopic-level plastic deformation and fracture of ion-modified Ni50Ti40Zr10 alloy with the shape-memory effect

The influence of the ion-modified surface layer on the ductility, shape-memory effect, and mesoscopic structure of the surface of fracture was studied for Ni₅₀Ti₄₀Zr₁₀ alloy. It was found that ion implantation increases the microhardness of the surface layer about 1 μm thick but makes the bulk of the alloy more ductile. The mesoscopic structures of the fracture surfaces of the initial and implanted specimens suggest the formation of a specific layer immediately under the irradiated surface. Its thickness is a multiple of the grain size of the B2 phase. The mesorelief of this layer and its ductile properties differ from those of the nonirradiated specimens. After such a surface treatment, the shape memory effect parameters do not degrade, and the temperature cycling resistance is even improved.     

Comparison of the supramolecular structures formed by a polymethacrylate with a highly tapered side chain and its monomeric precursor

Insight into the supramolecular structure formed by a polymethacrylate with a highly tapered side chain is obtained from parallel X-ray analysis of oriented fibers of the polymer and its monomeric precursor. The polymer is poly(2-{2-[2-(2-methacryloyloxyethoxy)ethoxy]ethoxy}ethyl 3,4,5-tris(p-dodecyloxybenzyloxy)benzoate) (abbreviated to 12-ABG-4EO-PMA); the monomeric precursor is the hydroxy-terminated side chain 2-{2-[2-(2-hydroxyethoxy)-ethoxy]ethoxy}ethyl 3,4,5-tris(p-dodecyloxybenzyloxy)benzoate (12-ABG-4EO-OH). The polymer and precursor both form ordered solid state structures that are converted to columnar hexagonal liquid crystalline (φ_h) phases at approximately 40°C and 50°C, respectively. The ordered solid state structures consist of ordered hexagonally packed cylindrical columns, in which the monomer units are probably packed with helical symmetry. For the polymer at 25°C, the column diameter is 60.4Å with an axial repeat of 5.03Å containing eight monomer units. For the precursor at 25°C, the column diameter is reduced to 53.5Å, probably due to the absence of the polymer backbone from the center of the column, and the axial repeat is doubled to 10.04Å. The X-ray data are compatible with a tighter winding of the monomers in a helical structure, but otherwise suggest that there are common features in the stacking of the aromatic groups in the two structures.     

Gene Interaction Network Analysis Reveals IFI44L as a Drug Target in Rheumatoid Arthritis and Periodontitis

Simple SummaryIn spite of substantial investigation, the biological link between periodontitis and rheumatoid arthritis remains unexplained. This study intended to correlate periodontitis and rheumatoid arthritis gene expression patterns to find shared targets for both the disease. We identified the differentially expressed genes (DEGs) in periodontitis and rheumatoid arthritis. The network was built by integrating DEGs and ranking the genes using GeneMANIA. FINDSITEcomb2.0 was used to find a possible inhibitor for the top-ranked gene. Further, the binding effectiveness and protein-ligand complex stability were then determined by molecular docking and molecular dynamics. The network analysis showed IFI44L as a highly ranking gene implicated in most immunological pathways. A virtual screening of 6507 compounds revealed vemurafenib as the best candidate for the IFI44L target. Molecular docking and molecular dynamics modelling revealed the stability of the IFI44L-vemurafenib complex, which suggest IFI44L is potential target and vemurafenib could be the better candidate to treat both diseases.AbstractObjective: Despite extensive research on periodontitis and rheumatoid arthritis, the underlying molecular connectivity between these condition remains largely unknown. This research aimed to integrate periodontitis and rheumatoid arthritis gene expression profiles to identify interconnecting genes and focus to develop a common lead molecule against these inflammatory conditions. Materials and Methods: Differentially expressed genes (DEGs) of periodontitis and rheumatoid arthritis were identified from the datasets retrieved from the Gene Expression Omnibus database. The network was constructed by merging DEGs, and the interconnecting genes were identified and ranked using GeneMANIA. For the selected top ranked gene, the potential inhibitor was searched using FINDSITE^comb2.0. Subsequently, the molecular docking and molecular dynamics were performed to determine the binding efficiency and protein-ligand complex stability, respectively. Results: From the network analysis, IFN-induced protein 44-like (IFI44L) was identified as a top ranked gene involved in most of the immunological pathway. With further virtual screening of 6507 molecules, vemurafenib was identified to be the best fit against the IFI44L target. The binding energy and stability of IFI44L with vemurafenib were investigated using molecular docking and molecular dynamics simulation. Docking results show binding energy of −7.7 Kcal/mol, and the simulation results show stability till 100 ns. Conclusions: The identified IFI44L may represent a common drug target for periodontitis and rheumatoid arthritis. Vemurafenib could be a potent anti-inflammatory drug for both diseases.     

Abscisic Acid—Defensive Player in Flax Response to Fusarium culmorum Infection

Fusarium culmorum is a ubiquitous soil pathogen with a wide host range. In flax (Linum ussitatissimum), it causes foot and root rot and accumulation of mycotoxins in flax products. Fungal infections lead to huge losses in the flax industry. Moreover, due to mycotoxin accumulation, flax products constitute a potential threat to the consumers. We discovered that the defense against this pathogen in flax is based on early oxidative burst among others. In flax plants infected with F. culmorum, the most affected genes are connected with ROS production and processing, callose synthesis and ABA production. We hypothesize that ABA triggers defense mechanism in flax and is a significant player in a successful response to infection.     

Tuning the local chemical environment of ZnSe quantum dots with dithiols towards photocatalytic CO2 reduction

Sunlight-driven CO₂ reduction to renewable fuels is a promising strategy towards a closed carbon cycle in a circular economy. For that purpose, colloidal quantum dots (QDs) have emerged as a versatile light absorber platform that offers many possibilities for surface modification strategies. Considerable attention has been focused on tailoring the local chemical environment of the catalytic site for CO₂ reduction with chemical functionalities ranging from amino acids to amines, imidazolium, pyridines, and others. Here we show that dithiols, a class of organic compounds previously unexplored in the context of CO₂ reduction, can enhance photocatalytic CO₂ reduction on ZnSe QDs. A short dithiol (1,2-ethanedithiol) activates the QD surface for CO₂ reduction accompanied by a suppression of the competing H₂ evolution reaction. In contrast, in the presence of an immobilized Ni(cyclam) co-catalyst, a longer dithiol (1,6-hexanedithiol) accelerates CO₂ reduction. ¹H-NMR spectroscopy studies of the dithiol-QD surface interactions reveal a strong affinity of the dithiols for the QD surface accompanied by a solvation sphere governed by hydrophobic interactions. Control experiments with a series of dithiol analogues (monothiol, mercaptoalcohol) render the hydrophobic chemical environment unlikely as the sole contribution of the enhancement of CO₂ reduction. Density functional theory (DFT) calculations provide a framework to rationalize the observed dithiol length dependent activity through the analysis of the non-covalent interactions between the dangling thiol moiety and the CO₂ reduction intermediates at the catalytic site. This work therefore introduces dithiol capping ligands as a straightforward means to enhance CO₂ reduction catalysis on both bare and co-catalyst modified QDs by engineering the particle''s chemical environment.

ZnSe quantum dots (yellow sphere) are modified with dithiols of various lengths for enhanced visible light-driven CO₂ to CO reduction in either the absence or presence of a molecular Ni co-catalyst.     

Phytochemical Profile and Biological Activity of the Ethanolic Extract from the Aerial Part of Crocus alatavicus Regel & Semen Growing Wildly in Southern Kazakhstan

The composition of the ethanolic extract from the aerial parts of Crocus alatavicus Regel & Semen from southern Kazakhstan spontaneous flora was analyzed together with the determination of its antibacterial, antifungal, antiviral and anticancer activity. The phytochemical profile analysis by high-performance liquid chromatography-electrospray ionization-quadrupole-time of flight-mass spectrometry (HPLC/ESI-QTOF-MS) revealed the presence of multiple kaempferol derivatives. High-performance reverse-phase liquid chromatography combined with a photodiode-array detection (RP-HPLC/PDA) found that kaempferol 3-O-dihexoside and kaempferol 3-O-acyltetrahexoside accounted for 70.5% of the kaempferol derivatives. The minimum inhibitory concentration (MIC) values of the extract for all the tested reference microorganisms were high, reaching 10 mg/mL for yeasts and 20 mg/mL for bacteria. In contrast, antiviral activity was observed at 2 mg/mL, resulting in the inhibition of the HSV-1-induced cytopathic effect and the reduction in virus infectious titer by 1.96 log, as well as the viral load by 0.85 log. Among the tested prostate cancer cell lines, significant cytotoxic activity of the extract was noted only on the LNCaP cell line, with an IC₅₀ value of 1.95 mg/mL. The LNCaP cell line treated with 2 mg/mL of the extract showed a noticeably reduced number of spindle-shaped cells with longer cellular projections, a significant increase in the peak corresponding to the population of apoptotic cells in the sub-G1 phase and a decreased intracellular glutathione (GSH) level, suggesting the prooxidative properties of the extract. The obtained data provide novel information about the flavonoids present in the aerial part of C. alatavicus and suggest its potential application as a source of the compounds active against HSV-1 and metastatic, androgen-sensitive prostate cancer.     

How To Make Nitroaromatic Compounds Glow: Next-Generation Large X-Shaped,Centrosymmetric Diketopyrrolopyrroles

Red-emissive π-expanded diketopyrrolopyrroles (DPPs) with fluorescence reaching λ=750 nm can be easily synthesized by a three-step strategy involving the preparation of diketopyrrolopyrrole followed by N-arylation and subsequent intramolecular palladium-catalyzed direct arylation. Comprehensive spectroscopic assays combined with first-principles calculations corroborated that both N-arylated and fused DPPs reach a locally excited (S₁) state after excitation, followed by internal conversion to states with solvent and structural relaxation, before eventually undergoing intersystem crossing. Only the structurally relaxed state is fluorescent, with lifetimes in the range of several nanoseconds and tens of picoseconds in nonpolar and polar solvents, respectively. The lifetimes correlate with the fluorescence quantum yields, which range from 6 % to 88 % in nonpolar solvents and from 0.4 % and 3.2 % in polar solvents. A very inefficient (T₁) population is responsible for fluorescence quantum yields as high as 88 % for the fully fused DPP in polar solvents.