Crystals of Diphenyl-Benzothiadiazole and Its Derivative with Terminal Trimethylsilyl Substituents: Growth from Solutions, Structure, and Fluorescence Properties.

Linear conjugated molecules consisting of benzothiadiazole (BTD) and phenyl rings are highly efficient organic luminophores. Crystals based on these compounds have great potential for use as light-emitting elements, in particular, scintillation detectors. This paper compares the peculiarities of growth, structure, and fluorescent properties of crystals based on 4,7-diphenyl-2,1,3-benzothiadiazole (P2-BTD) and its organosilicon derivative 4,7-bis(4-(trimethylsilyl)phenyl) BTD ((TMS-P)2-BTD). The conditions for the formation of centimeter-scale single crystals were found for the former, while it was possible to prepare also bulky faceted individual crystals for the latter. The structures of P2-BTD and (TMS-P)2-BTD crystals at 85 and 293 K were investigated by single-crystal X-ray diffraction. The crystal structure of P2-BTD has been refined (sp. gr. P1̅, Z = 4), and for (TMS-P)2-BTD crystals, the structure has been solved for the first time (sp. gr. P21/c, Z = 32). Experimental and theoretical investigations of the absorption-fluorescent properties of solutions and crystals of the molecules have been carried out. The luminophores are characterized by a large Stokes shift for both solutions and crystals with a high fluorescence quantum yield of 75-98% for solutions and 50-85% for the crystals. A solvatochromic effect was observed for solutions of both luminophores: an increase in the values of the fluorescence quantum yield and the excited state lifetime were established with increasing the solvent polarity. Fluorescence properties of solutions and crystals have been analyzed using the data on crystal structure and conformation structure of the molecules as well as density functional theory calculations of their electronic structure. The results have shown that the crystal packing of P2-BTD molecules exhibits uniformity in conformational states, while (TMS-P)2-BTD molecules display a variety of conformational structures in the crystals. This unique combination of features makes them a remarkable example among the other molecular systems for identifying the relationship between the structure and absorption-fluorescence properties through comparative analysis.

Synthesis and Photophysical Properties of Novel Meta-Conjugated Organic Molecules with 1,3,5-Benzene Branching Units.

The synthesis and photophysical investigation of three novel meta-conjugated molecules based on 3,1,2-benzothiadiazole and thiophene-2,5-diyl derivatives linked through 1,3,5-benzene branching units are described. Each of them is a symmetrical molecule with two branching units, four identical lateral thiophene-containing fragments, and one central benzothiadiazole-containing fragment. To study the effect of the chemical structure on their photophysical properties, the molecules with different linearly conjugated lateral and central fragments due to incorporation of additional thiophene rings were synthesized and compared. It was shown that absorption spectra of the meta-conjugated molecules can be represented as a sum of absorption bands of model compounds for their peripheral and central fragments containing a common benzene ring being branched at the 1,3,5-benzene unit in the meta-conjugated molecules. Therefore, they cannot be considered simply as isolated π-conjugated systems of their peripheral and central fragments. Instead, DFT calculations showed that several transitions between the orbitals located in different regions of the meta-conjugated molecule are responsible for the formation of their absorption spectra, and they strongly depend on the degree of their overlapping. Theoretical absorption spectra reconstructed from the DFT data demonstrated a good agreement with the experimental results: the transitions with larger oscillator strength correspond to the bands with higher molar extinction coefficients and vice versa. It was shown that luminescence spectral maxima of the meta-conjugated molecules monotonically shift to the lower energy from 489 to 540 and 613 nm with increasing the number of thiophene rings in the peripheral and central fragments, respectively. However, luminescence quantum yield of the meta-conjugated molecules critically depends on the length of linearly conjugated fragments in its structure decreasing from 24% to 1.3% with increasing the number of thiophene rings in the lateral fragments but increasing to 90% in the molecule with more thiophene rings in both types of the fragments. The results obtained are well correlated to the ratio of radiative and nonradiative deactivation rate constants of the meta-conjugated molecules that indicates a high rate of internal conversion between the excited states corresponding to different fragments of the molecule. The CV measurements allowed estimating the HOMO, LUMO, and bandgap values of the target and model compounds, which confirm the presence of meta-conjugation within the molecules investigated. Thus, connection of linearly conjugated fragments through meta-positions (meta-conjugation) of a benzene ring leads to an intermediate option between fully conjugated and nonconjugated molecules due to partial delocalization of electron density through the 1,3,5-substituted benzene branching center.

Computational characterization of the glutamate receptor antagonist perampanel and its close analogs: density functional exploration of conformational space and molecular docking study.

Perampanel approved by FDA in 2012 is a first-in-class antiepileptic drug which inhibits α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents. It is markedly more active than many of its close analogs, and the reasons for this activity difference are not quite clear. Recent crystallographic studies allowed the authors to identify the location of its binding site. Unfortunately, the resolution is low, and the detailed description of perampanel binding mode is still in part speculative. Here we provide a detailed DFT-level conformational analysis of perampanel in a vacuum and in the solvents, mimicking the protein environment, followed by quantum theory of atoms in molecules (QTAIM), non-covalent interactions (NCI), and natural bond orbital (NBO) analyses. The findings indicate the electrostatic nature of the intramolecular interactions which contribute to energy differences of the conformations in a vacuum whereas the increase of dielectric constant leads to the energy equalization of conformations. Based on these results, the docking study was performed to investigate possible binding modes of perampanel and its close analogs in AMPA receptors. The influence of the pyridine nitrogen and cyano group position was explained based on the results of conformational analysis and molecular docking. These findings may contribute to the design of novel antiepileptic drugs and the development of novel approaches to treat neurodegenerative diseases and major depressive disorder.

General Purpose Electronegativity Relaxation Charge Models Applied to CoMFA and CoMSIA Study of GSK-3 Inhibitors.

Two fast empirical charge models, Kirchhoff Charge Model (KCM) and Dynamic Electronegativity Relaxation (DENR), had been developed in our laboratory previously for widespread use in drug design research. Both models are based on the electronegativity relaxation principle (Adv. Quantum Chem. 2006, 51, 139-156) and parameterized against ab initio dipole/quadrupole moments and molecular electrostatic potentials, respectively. As 3D QSAR studies comprise one of the most important fields of applied molecular modeling, they naturally have become the first topic to test our charges and thus, indirectly, the assumptions laid down to the charge model theories in a case study. Here these charge models are used in CoMFA and CoMSIA methods and tested on five glycogen synthase kinase 3 (GSK-3) inhibitor datasets, relevant to our current studies, and one steroid dataset. For comparison, eight other different charge models, ab initio through semiempirical and empirical, were tested on the same datasets. The complex analysis including correlation and cross-validation, charges robustness and predictability, as well as visual interpretability of 3D contour maps generated was carried out. As a result, our new electronegativity relaxation-based models both have shown stable results, which in conjunction with other benefits discussed render them suitable for building reliable 3D QSAR models.