Hydrogen bonding patterns and C-H...π interactions in the structure of the antiparkinsonian drug (R)-rasagiline mesylate determined using laboratory and synchrotron X-ray powder diffraction data.

The structure of (R)-rasagiline mesylate [(R)-RasH+·Mes-], an active pharmaceutical ingredient used to treat Parkinson's disease, is presented. The structure was determined from laboratory and synchrotron powder diffraction data, refined using the Rietveld method, and validated and optimized using dispersion-corrected DFT calculations. The unit-cell parameters obtained in both experiments are in good agreement and the refinement with both datasets converged to good agreement factors. The final parameters obtained from laboratory data were a = 5.4905 (8), b = 6.536 (2), c = 38.953 (3) Å, V = 1398.0 (4) Å3 and from synchrotron powder data were a = 5.487530 (10) Å, b = 6.528939 (12) Å, c = 38.94313 (9) Å, V = 1395.245 (5) Å3 with Z = 4 and space group P212121. Preferred orientation was properly accounted for using the synchrotron radiation data, leading to a March-Dollase parameter of 1.140 (1) instead of the 0.642 (1) value obtained from laboratory data. In the structure, (R)-RasH+ moieties form layers parallel to the ab plane connected by mesylate ions through N-H...O and C-H...O hydrogen bonds. These layers stack along the c axis and are further connected by C-H...π interactions. Hirshfeld surface analysis and fingerprint plot calculations indicate that the main interactions are: H...H (50.9%), H...C/C...H (27.1%) and H...O/O...H (21.1%).

Crystal structure from X-ray powder diffraction data, DFT-D calculation, Hirshfeld surface analysis, and energy frameworks of (RS)-trichlorme-thia-zide.

The structure of racemic (RS)-trichlorme-thia-zide [systematic name: (RS)-6-chloro-3-(di-chloro-meth-yl)-1,1-dioxo-3,4-di-hydro-2H-1λ6,2,4-benzo-thia-di-azine-7-sulfonamide], C8H8Cl3N3O4S2 (RS-TCMZ), a diuretic drug used in the treatment of oedema and hypertension, was determined from laboratory X-ray powder diffraction data using DASH [David et al. (2006 ▸). J. Appl. Cryst. 39, 910-915.], refined by the Rietveld method with TOPAS-Academic [Coelho (2018 ▸). J. Appl. Cryst. 51, 210-218], and optimized using DFT-D calculations. The extended structure consists of head-to-tail dimers connected by π-π inter-actions which, in turn, are connected by C-Cl⋯π inter-actions. They form chains propagating along [101], further connected by N-H⋯O hydrogen bonds to produce layers parallel to the ac plane that stack along the b-axis direction, connected by additional N-H⋯O hydrogen bonds. The Hirshfeld surface analysis indicates a major contribution of H⋯O and H⋯Cl inter-actions (32.2 and 21.7%, respectively). Energy framework calculations confirm the major contribution of electrostatic inter-actions (E elec) to the total energy (E tot). A comparison with the structure of S-TCMZ is also presented.

GABAA receptor family: overview on structural characterization.

The pentameric γ-aminobutyric acid type A receptors are ion channels activated by ligands, which intervene in the rapid inhibitory transmission in the mammalian CNS. Due to their rich pharmacology and therapeutic potential, it is essential to understand their structure and function thoroughly. This deep characterization was hampered by the lack of experimental structural information for many years. Thus, computational techniques have been extensively combined with experimental data, in order to undertake the study of γ-aminobutyric acid type A receptors and their interaction with drugs. Here, we review the exciting journey made to assess the structures of these receptors and outline major outcomes. Finally, we discuss the brand new structure of the α1ß2γ2 subtype and the amazing advances it brings to the field.

Kinetic and equilibrium adsorption of two post-harvest fungicides onto copper-exchanged montmorillonite: synergic and antagonistic effects of both fungicides' presence.

The simultaneous adsorption of both imazalil (IMZ) and thiabendazole (TBZ) fungicides in a Cu2+-exchanged Mt was studied in this work. Kinetic studies were used to determine the rate law which describes the adsorption of individual fungicides onto the adsorbent. Adsorption isotherm of individual and combined fungicides was done to evaluate synergic or antagonistic effects. The Mt-Cu material considerably improved TBZ and/or IMZ adsorption from aqueous suspensions with respect to raw Mt, leading to removal efficiencies higher than 99% after 10 min of contact time for TBZ and IMZ Ci = 15 and 40 mg/L, respectively, when a solid dosage = 1 g/L was used. The adsorption sites involved were determined by a combination of X-ray diffraction (XRD) determinations and electron paramagnetic resonance (EPR), indicating that fungicides were bonded to Cu2+ cations, while the rate limiting step was the formation of coordination bonds. The adsorption mechanism proposed is that of ligand exchange between water and fungicide molecules in the metal coordination sphere. The single-crystal structure for the IMZ-Cu2+ complex indicated that four molecules were bounded to the copper centers, while two molecules of TBZ are bounded to copper explaining the higher IMZ uptake capacity for the Mt-Cu material. Graphical abstract.

Design, Synthesis, Experimental and Theoretical Characterization of a New Multitarget 2-Thienyl-N-Acylhydrazone Derivative.

Pulmonary arterial hypertension (PAH) is a chronic cardiovascular disease that displays inflammatory components, which contributes to the difficulty of adequate treatment with the available therapeutic arsenal. In this context, the N-acylhydrazone derivative LASSBio-1359 was previously described as a multitarget drug candidate able to revert the events associated with the progression of PAH in animal models. However, in spite of having a dual profile as PDE4 inhibitor and adenosine A2A receptor agonist, LASSBio-1359 does not present balanced potencies in the modulation of these two targets, which difficult its therapeutic use. In this paper, we describe the design concept of LASSBio-1835, a novel structural analogue of LASSBio-1359, planned by exploiting ring bioisosterism. Using X-ray powder diffraction, calorimetric techniques, and molecular modeling, we clearly indicate the presence of a preferred synperiplanar conformation at the amide function, which is fixed by an intramolecular 1,5-N∙∙∙S σ-hole intramolecular interaction. Moreover, the evaluation of LASSBio-1835 (4) as a PDE4 inhibitor and as an A2A agonist confirms it presents a more balanced dual profile, being considered a promising prototype for the treatment of PAH.

Structure and interaction of Corynebacterium pseudotuberculosis cold shock protein A with Y-box single-stranded DNA fragment.

Cold shock proteins (Csps) function to preserve cell viability at low temperatures by binding to nucleic acids and consequently control gene expression. The mesophilic bacterium Corynebacterium pseudotuberculosis is the causative agent of caseous lymphadenitis in animals, and infection in livestock is a considerable economic burden worldwide. In this report, the structure of cold shock protein A from Cp (Cp-CspA) and biochemical analysis of its temperature-dependent interaction with a Y-box ssDNA motif is presented. The Cp-CspA structure contains five ß-strands making up a ß-barrel fold with 11 hydrophobic core residues and two salt bridges that confers it with a melting temperature of ~ 54 °C that is similar to mesophilic Bs-CspB. Chemical shift perturbations analysis revealed that residues in the nucleic acid-binding motifs (RNP 1 and 2) and loop 3 are involved in binding to the Y-box fragment either by direct interaction or by conformational rearrangements remote from the binding region. Fluorescence quenching experiments of Cp-CspA showed that the dissociation constants for Y-box ssDNA binding is nanomolar and the binding affinity decreased as the temperature increased, indicating that the interaction is enthalpically driven and the hydrogen bonds and van der Waals forces are important contributions for complex stabilization. The Y31 of Cp-CspA is a particular occurrence among Csps from mesophilic bacteria that provide a possible explanation for the higher binding affinity to ssDNA than that observed for Bs-CspB. Anisotropy measurements indicated that the reduction in molecular mobility of Cp-CspA upon Y-box binding is characterized by a cooperative process. DATABASE: Resonance assignment and structural data are available in the Biological Magnetic Resonance Data Bank and Protein Data Bank under accession number 26802 and 5O6F, respectively.

Understanding the conformational changes and molecular structure of furoyl thioureas upon substitution.

1-Acyl thioureas [R1C(O)NHC(S)NR2R3] are shown to display conformational flexibility depending on the degree of substitution at the nitrogen atom. The conformational landscape and structural features for two closely related thioureas having R1=2-furoyl have been studied. The un-substituted 2-furoyl thiourea (I) and its dimethyl analogue, i.e. 1-(2-furoyl)-3,3-dimethyl thiourea (II), have been synthesized and fully characterized by spectroscopic (FT-IR, 1H and 13C NMR) and elemental analysis. According to single crystal X-ray diffraction analysis, compounds I and II crystallize in the monoclinic space group P21/c. In the compound I, the trans-cis geometry of the almost planar thiourea unit is stabilized by intramolecular NH⋯OC hydrogen bond between the H atom of the cis thioamide and the carbonyl O atom. In compound II, however, the acyl thiourea group is non-planar, in good agreement with the potential energy curve computed at the B3LYP/6-31+G(d,p) level of approximation. Centrosymmetric dimers generated by intermolecular NH⋯SC hydrogen bond forming R22(8) motif are present in the crystals. Intermolecular interactions have been rationalized in terms of topological partitions of the electron distributions and Hirshfeld surface analysis, which showed the occurrence of S⋯H, O⋯H and H⋯H contacts that display an important role to crystal packing stabilization of both thiourea derivatives.

Synthesis, crystal structure, conformational and vibrational properties of 6-acetyl-2,2-dimethyl-chromane.

The 6-acetyl-2,2-dimethyl-chromane compound was synthesized and characterized by IR, Raman, UV-Visible and (1)H NMR spectroscopies. Its solid state structure was determined by X-ray diffraction methods. The substance crystallizes in the triclinic P-1 space group with a=5.9622(5) Å, b=10.342(1) Å, c=10.464(1) Å, α=63.81(1)°, ß=81.923(9)°, γ=82.645(9)°, and Z=2 molecules per unit cell. Due to extended π-bonding delocalization a substantial skeletal fragment of the molecule is planar. The vibrational modes were calculated at B3LYP/6-31G(d,p) level and all of them assigned in the IR and Raman spectra. The DFT calculated (1)H NMR spectrum (chemical shifts) were in good agreement with the experimental data. The electronic (UV-Visible) spectrum was calculated using TD-DFT method in gas phase and it was correlated with the experimental data. The assignment and analysis of the frontier HOMO and LUMO orbitals indicate that the absorption bands are mainly originated from π→π(*) transitions. According to DSC measurements the substance presents a melting point of 93°C and decomposes at temperatures higher than 196°C.