The Benzothiazine Core as a Novel Motif for DNA-Binding Small Molecules.

A new series of 4H-1,3-benzothiazine dyes were prepared and fully characterized in an aqueous medium. Benzothiazine salts were synthesized either through the classical synthetic pathway using Buchwald-Hartwig amination or through economical and environmentally friendly electrochemical synthesis. The latest synthetic approach employs successful electrochemical intramolecular dehydrogenative cyclization of N-benzylbenzenecarbothioamides to form 4H-1,3-benzothiazines. 4H-1,3-Benzothiazines were evaluated as novel DNA/RNA probes. Through the use of several methods such as UV/vis spectrophotometric titrations, circular dichroism and thermal melting experiments, the binding of four benzothiazine-based molecules to polynucleotides was examined. Compounds 1 and 2 acted as DNA/RNA groove binders, thus suggesting the potential of these compounds as novel DNA/RNA probes. This is a proof-of-concept study and will be expanded to include SAR/QSAR studies.

The nature of π-hole interactions between iodide anions and quinoid rings in the crystalline state.

The investigated co-crystal of 3-chloro-N-methylpyridinium iodide with tetrabromoquinone (3-Cl-N-MePy·I·Br4Q) reveals a π-hole interaction between an iodide anion and a quinoid ring involving an n → π* charge transfer. The quinoid ring has a partial negative charge (estimated to be in the range 0.08-0.11e) and a partial radical character, which is related to the black colour of the crystals (crystals of neutral tetrabromoquinone are yellow). A detailed X-ray charge density study revealed two symmetry-independent bond critical points between the iodide anions and carbon atoms of the ring. Their maximum electron density of 0.065 e Å-3 was reproduced by quantum chemical modelling. The energy of the interaction is estimated to be -11.16 kcal mol-1, which is comparable to the strength of moderate hydrogen bonding (about -10 kcal mol-1); it is dominantly electrostatic in nature, with a considerable dispersion component.

Resveratrol-Maltol and Resveratrol-Thiophene Hybrids as Cholinesterase Inhibitors and Antioxidants: Synthesis, Biometal Chelating Capability and Crystal Structure.

New resveratrol-thiophene and resveratrol-maltol hybrids were synthesized as cholinesterase inhibitors and antioxidants. As with photostability experiments, biological tests also found remarkable differences in the properties and behavior of thiophene and maltol hybrids. While resveratrol-thiophene hybrids have excellent inhibitory and antioxidant properties (similar to the activity of reference drug galantamine), maltols have been proven to be weaker inhibitors and antioxidants. The molecular docking of selected active ligands gave insight into the structures of docked enzymes. It enabled the identification of interactions between the ligand and the active site of both cholinesterases. The maltols that proved to be active cholinesterase inhibitors were able to coordinate Fe3+ ion, forming complexes of 1:1 composition. Their formation constants, determined by spectrophotometry, are very similar, lgK = 11.6-12.6, suggesting that Fe3+ binds to the common hydroxy-pyranone moiety and is hardly affected by the other aromatic part of the ligand. Accordingly, the characteristic bands in their individual absorption spectra are uniformly red-shifted relative to those of the free ligands. The crystal structures of two new resveratrol-maltol hybrids were recorded, giving additional information on the molecules' intermolecular hydrogen bonds and packing. In this way, several functionalities of these new resveratrol hybrids were examined as a necessary approach to finding more effective drugs for complicated neurodegenerative diseases.

Hydrogen Bonding Drives Helical Chirality via 10-Membered Rings in Dipeptide Conjugates of Ferrocene-1,1'-Diamine.

Considering the enormous importance of protein turns as participants in various biological events, such as protein-protein interactions, great efforts have been made to develop their conformationally and proteolytically stable mimetics. Ferrocene-1,1'-diamine was previously shown to nucleate the stable turn structures in peptides prepared by conjugation with Ala (III) and Ala-Pro (VI). Here, we prepared the homochiral conjugates of ferrocene-1,1'-diamine with l-/d-Phe (32/35), l-/d-Val (33/36), and l-/d-Leu (34/37) to investigate (1) whether the organometallic template induces the turn structure upon conjugation with amino acids, and (2) whether the bulky or branched side chains of Phe, Val, and Leu affect hydrogen bonding. Detailed spectroscopic (IR, NMR, CD), X-ray, and DFT studies revealed the presence of two simultaneous 10-membered interstrand hydrogen bonds, i.e., two simultaneous ß-turns in goal compounds. A preliminary biological evaluation of d-Leu conjugate 37 showed its modest potential to induce cell cycle arrest in the G0/G1 phase in the HeLa cell line but these results need further investigation.

Semiconductive 2D arrays of pancake-bonded oligomers of partially charged TCNQ radicals.

Multicentre two-electron (mc/2e or 'pancake bonding') bonding between 7,7,8,8-tetra-cyano-quinodi-methane (TCNQ) radical anions was studied on its 14 novel salts with planar organic cations. The formal charges of the TCNQδ- moieties are -1/2 and -2/3, and they form mc/2e bonded dimers, trimers and tetramers which are further stacked into extended arrays. Multicentre bonding within these oligomers is characterized by short interplanar separations of 2.9-3.2 Å; distances between the oligomers are larger, typically >3.3 Å. The stacks are laterally connected by C-H⋯N hydrogen bonding, forming 2D arrays. The nature of mc/2e bonding is characterized by structural, magnetic and electrical data. The compounds are found to be semiconductors, and high conductivity [10-2 (Ω cm)-1] correlates with short interplanar distances between pancake-bonded oligomers.

Charge density studies of multicentre two-electron bonding of an anion radical at non-ambient temperature and pressure.

The variation of charge density of two-electron multicentre bonding (pancake bonding) between semi-quinone radicals with pressure and temperature was studied on a salt of 5,6-di-chloro-2,3-di-cyano-semi-quinone radical anion (DDQ) with 4-cyano-N-methyl-pyridinium cation (4-CN) using the Transferable Aspheric Atom Model (TAAM) refinement. The pancake-bonded radical dimers are stacked by non-bonding π-interactions. With rising pressure, the covalent character of interactions between radicals increases, and above 2.55 GPa, the electron density indicates multicentric covalent interactions throughout the stack. The experimental charge densities were verified and corroborated by periodic DFT computations. The TAAM approach has been tested and validated for atomic resolution data measured at ambient pressure; this work shows this approach can also be applied to diffraction data obtained at pressures up to several gigapascals.

Pancake-bonding of semiquinone radicals under variable temperature and pressure conditions.

The effects of temperature (100-370 K) and pressure (0-6 GPa) on the non-localized two-electron multicentric covalent bonds (`pancake bonding') in closely bound radical dimers were studied using single-crystal X-ray diffraction on a 4-cyano-N-methylpyridinium salt of 5,6-dichloro-2,3-dicyanosemiquinone radical anion (DDQ) as the sample compound. On cooling, the anisotropic structural compression was accompanied by continuous changes in molecular stacking; the discontinuities in the changes in volume and b and c cell parameters suggest that a phase transition occurs between 210 and 240 K. At a pressure of 2.55 GPa, distances between radical dimers shortened to 2.9 Å, which corresponds to distances observed in extended π-bonded polymers. Increasing pressure further to 6 GPa reduced the interplanar separation of the radicals to 2.75 Å. This may indicate that the covalent component of the interaction significantly increased, in accordance with the results of DFT calculations reported elsewhere [Molcanov et al. (2019), Cryst. Growth Des. 19, 391-402].

A simple and easy to perform synthetic route to functionalized thienyl bicyclo[3.2.1]octadienes.

In order to prepare novel polycyclic derivatives of bicyclo[3.2.1]octadiene systems fused with a thiophene ring, photochemical cyclization and aldol condensation reactions were carried out. The starting substrates were easily obtained by a Vilsmeier-Haack reaction of bicyclo[3.2.1]octadiene thiophene derivatives with dimethylformamide. From the obtained carbaldehydes, novel methyl, methoxy, and cyano-substituted styryl thienobenzobicyclo[3.2.1]octadiene derivatives were synthesized through Wittig reactions and subjected to photochemical cyclization, in terms of obtaining the new annulated structures. As part of this study, the aldol reaction of the starting 2-substituted carbaldehyde with acetone was also performed, which produced the thieno-fused benzobicyclo[3.2.1]octadiene compound with an extended conjugation.