Identification of Novel Antistaphylococcal Hit Compounds Targeting Sortase A

Staphylococcus aureus (S. aureus) is a causative agent of many hospital- and community-acquired infections with the tendency to develop resistance to all known antibiotics. Therefore, the development of novel antistaphylococcal agents is of urgent need. Sortase A is considered a promising molecular target for the development of antistaphylococcal agents. The main aim of this study was to identify novel sortase A inhibitors. In order to find novel antistaphylococcal agents, we performed phenotypic screening of a library containing 15512 compounds against S. aureus ATCC43300. The molecular docking of hits was performed using the DOCK program and 10 compounds were selected for in vitro enzymatic activity inhibition assay. Two inhibitors were identified, N,N-diethyl-N′-(5-nitro-2-(quinazolin-2-yl)phenyl)propane-1,3-diamine (1) and acridin-9-yl-(1H-benzoimidazol-5-yl)-amine (2), which decrease sortase A activity with IC₅₀ values of 160.3 µM and 207.01 µM, respectively. It was found that compounds 1 and 2 possess antibacterial activity toward 29 tested multidrug resistant S. aureus strains with MIC values ranging from 78.12 to 312.5 mg/L. These compounds can be used for further structural optimization and biological research.     

Fermi Arcs and DC Transport in Nanowires of Dirac and Weyl Semimetals

The transport properties and electron states in cylinder nanowires of Dirac and Weyl semimetals are studied paying special attention to the structure and properties of the surface Fermi arcs. The latter make the electric charge and current density distributions in nanowires strongly nonuniform as the majority of the charge density is accumulated at the surface. It is found that a Weyl semimetal wire also supports a magnetization current localized mainly at the surface because of the Fermi arcs contribution. By using the Kubo linear response approach, the direct current (DC) conductivity is calculated and it is found that its spatial profile is nontrivial. By explicitly separating the contributions of the surface and bulk states, it is shown that when the electric chemical potential and/or the radius of the wire is small, the electron transport is determined primarily by the Fermi arcs and the electrical conductivity is much higher at the surface than in the bulk. Due to the rise of the surface-bulk transition rate, the relative contribution of the surface states to the total conductivity gradually diminishes as the chemical potential increases. In addition, the DC conductivity at the surface demonstrates noticeable peaks when the Fermi level crosses energies of the surface states.     

Microwave-Assisted Synthesis of Modified Glycidyl Methacrylate–Ethyl Methacrylate Oligomers,Their Physico-Chemical and Biological Characteristics

In this study, well-known oligomers containing ethyl methacrylate (EMA) and glycidyl methacrylate (GMA) components for the synthesis of the oligomeric network [P(EMA)-co-(GMA)] were used. In order to change the hydrophobic character of the [P(EMA)-co-(GMA)] to a more hydrophilic one, the oligomeric chain was functionalized with ethanolamine, xylitol (Xyl), and L-ornithine. The oligomeric materials were characterized by nuclear magnetic resonance and Fourier transform infrared spectroscopy, scanning electron microscopy, and differential thermogravimetric analysis. In the final stage, thanks to the large amount of -OH groups, it was possible to obtain a three-dimensional hydrogel (HG) network. The HGs were used as a matrix for the immobilization of methylene blue, which was chosen as a model compound of active substances, the release of which from the matrix was examined using spectrophotometric detection. The cytotoxic test was performed using fluid extracts of the HGs and human skin fibroblasts. The cell culture experiment showed that only [P(EMA)-co-(GMA)] and [P(EMA)-co-(GMA)]-Xyl have the potential to be used in biomedical applications. The studies revealed that the obtained HGs were porous and non-cytotoxic, which gives them the opportunity to possess great potential for use as an oligomeric network for drug reservoirs in in vitro application.     

Modified Isoindolediones as Bright Fluorescent Probes for Cell and Tissue Imaging

New L -shaped fluorophores possessing five conjugated rings have been synthesized through a four-step procedure involving diketopyrrolopyrrole synthesis and its double N-alkylation, followed by trimethylsilyl bromide-mediated rearrangement to thieno[2,3-f]isoindole-5,8-dione and an intramolecular Friedel–Crafts reaction. In comparison with the parent isoindolediones and π-expanded diketopyrrolopyrroles, these new dyes show red-shifted absorption and emission (up to ≈630 nm). Their structural rigidity is responsible for both the observed small Stokes shifts and large fluorescence quantum yields. Tissue imaging studies revealed that these new dyes show advantageous features including minimal autofluorescence interference and pronounced solvent-sensitive emission. Interestingly, there is a fundamental difference between a dye possessing an amino group and its analog bearing an N-alkyl substituent. The former dye under two-photon excitation at 900 nm gives bright images whereas its N-alkylated counterpart does not. A new type of membrane localization has been discovered by an N-alkylated isoindoledione possessing a benzofuryl substituent. In spite of the fact that the fluorescence quantum yield of this dye in a range of solvents is rather low, it does stain cell membranes exclusively. This new mode of cellular staining opens the door towards further development of membrane staining dyes.     

Azaarene Dimers

Binaphthyl-3,3′,4,4′-tetraone was prepared and coupled to different bis(TIPS-ethynyl)-substituted (TIPS=triisopropyl silane) aromatic diamines, resulting in the formation of dimeric benzo-fused azaacenes, centrally connected by a single bond. The two halves of the molecules are highly twisted with respect to each other and showed limited electronic interaction in the ground state because their absorption spectra remained very similar to those of the constituting monomers. The dimers displayed greatly reduced fluorescence when compared to the monomers, suggesting that there is a significant interaction of the two azarene units in the excited state. Preliminary investigations showed that the dimers are attractive for application as acceptors in organic photovoltaic because they significantly outperform their monomeric counterparts.     

Towards Nonalternant Nanographenes through Self-Promoted Intramolecular Indenoannulation Cascade by C−F Bond Activation

Large polycyclic aromatic hydrocarbons (PAHs) containing pentagons represent an important class of compounds that are considered to be superior materials in future nano-electronic applications. From this perspective, the development of synthetic approaches to large PAHs and nanographenes (NGs) is a matter of great importance. In this context indenoannulation appears to be the most practical way to introduce pentagons into NGs. Here we report that alumina-mediated C−F bond activation is an attractive tool for the synthesis of non-alternant NGs bearing several pentagons. The unique nature of the reaction leads to a rather counter-intuitive outcome and allows considering each previous aryl–aryl coupling as a promoter of the following one, despite the continuous increase in the strain energy. Thus, the presented strategy combines both facile synthesis and significant yields for large nonalternant PAHs and NGs.     

C6-substituted analogues of 8-azanebularine: probes of an RNA-editing enzyme active site

[reaction: see text] We describe the synthesis of derivatives of 8-azanebularine, a known inhibitor of adenosine deaminases including the RNA-editing enzyme ADAR2. 6-Methyl, 6-hydroxymethyl, 6-cyano, and 6-mercapto derivatives were obtained from 6-bromo precursors using different cross-coupling or substitution reactions. The C6-methyl derivative was incorporated into an RNA substrate for ADAR2 via the phosphoramidite. Quantitative gel mobility shift experiments with the resulting RNA indicate that methylation at C6 dramatically reduces the affinity of 8-azanebularine for ADAR2.     

Tetrabenzononacene: “Butterfly Wings” Stabilize the Core

In combination with bulky substituents at the core, fourfold benzannulation at the cata‐positions stabilizes a nonacene sufficiently to allow its isolation and characterization by ¹H NMR and X‐ray analysis. The four benzo units blueshift the absorption spectrum in comparison to a solely linear nonacene, but significantly increase the stability in the solid state.     

Modular Synthesis of Spirocyclic Germafluorene–Germoles: A New Family of Tunable Luminogens

The zirconium‐mediated synthesis of a new class of air‐stable spirocyclic germafluorene–germole (SGG) luminogens is reported. These species contain ring‐fused germafluorene and germole units that display color‐tunable fluorescence when peripheral aryl substituents are appended. Three distinct pathways are introduced for SGG modification (Stille, Suzuki–Miyaura, and zirconocene‐mediated couplings), which enable the preparation of new libraries of molecular and polymeric SGG light‐emitters with tunable luminescence and desirable thermal‐ and photo‐stability.