3,5,7-Trimeth­oxy-2-(4-methoxy­phen­yl)-4H-1-benzopyran-4-one

In the title compound, C19H18O6, also known as 3,4′,5,7-tetra­methoxy­flavone, the dihedral angle between the benzopyran-4-one group and the attached benzene ring is 11.23 (8)°. An intra­molecular C—H⋯O hydrogen bond generates an S(6) ring motif. In the crystal, mol­ecules are linked into a two-dimensional network parallel to (01) by inter­molecular C—H⋯O hydrogen bonds, which generate R 4 4(20), R 4 4(12) and R 2 2(14) ring motifs. Adjacent networks interact by π–π inter­actions between the pyran ring and its methoxy­phenyl substituent [centroid–centroid distance = 3.5267 (8) Å]

5,7-Dimeth­oxy-2-(4-methoxy­phen­yl)-4H-1-benzopyran-4-one methanol solvate monohydrate

In the title compound (alternatively called 4′,5,7-trimethoxy­flavone methanol solvate hydrate), C18H16O5·CH3OH·H2O, the flavone mol­ecule is almost planar, the inter­planar angle between the planes of the benzopyran-4-one group and the attached benzene ring being 4.69 (9)°. In the crystal, the flavone mol­ecule makes inter­molecular C—H⋯O hydrogen bonds to adjacent inversion-related flavone mol­ecules, generating R 2 2(8) and R 2 2(14) rings and an infinite ribbon. The inversion-related ribbons are stabilized through the inter­stitial water and methanol mol­ecules via inter­molecular O—H⋯O hydrogen bonds, generating R 4 2(8) and R 2 1(6) rings and C 2 2(4) chains, and are further sustained by π–π inter­actions with an inter­planar spacing of 3.365 (2)Å

(E)-2,4,7-Trichloro-3-hydr­oxy-8-meth­oxy-1,9-dimethyl-6-(1-methyl-1-propen­yl)-11H-dibenzo[b,e][1,4]dioxepin-11-one monohydrate (nidulin monohydrate)

In the title compound, C20H17Cl3O5·H2O, the nidulin mol­ecule consists of three rings, the folded central dioxepin-11-one ring being fused on both sides to phenyl rings. The mol­ecular structure is stabilized by intra­molecular O—H⋯Cl and C—H⋯Cl hydrogen bonds that generate S(6) ring motifs. The crystal structure is stabilized by inter­molecular O—H⋯O and O—H⋯(O,O) hydrogen bonds mediated by two inversion-related water mol­ecules, generating R 4 2(8) ring and C 2 2(4) chain motifs. Weak inter­molecular Cl⋯O halogen bonds are also present with Cl⋯O distances of 3.071 (1) and 3.182 (2) Å

6-Butyryl-5-hy­droxy-4-phenyl­seselin

In the title coumarin compound (systematic name: 6-butyryl-5-hy­droxy-8,8-dimethyl-4-phenyl-2H,8H-benzo[1,2-b;3,4-b′]dipyran-2-one), C24H22O5, also known as mammea A/AC cyclo D, the chromene and pyran rings are almost coplanar with a maximum deviation from the mean plane of 0.295 (2) Å. The attached phenyl group is inclined at 53.49 (8)° with respect to the chromene ring. The mol­ecular structure is stabilized by an intra­molecular O—H⋯O hydrogen bond. In the crystal, mol­ecules are linked into sheets parallel to (101) by inter­molecular C—H⋯O hydrogen bonds. Adjacent sheets are sustained by inter­molecular C—H⋯π and π–π [centroid–centroid distance = 4.471 (2) Å] inter­actions

Paraherquamide E

In the title compound, C28H35N3O4, also known as 14-de­oxy­paraherquamide A,the two pyrrolidine rings adopt envelope conformations. The piperazine ring of the diaza­bicyclo­[2.2.2]octan-3-one unit adopts a boat conformation whereas the two piperidine rings are in distorted boat conformations. Intra­molecular C—H⋯O hydrogen bonds are observed. In the crystal, the mol­ecules are linked into chains along the b axis by inter­molecular N—H⋯O hydrogen bonds

Untersuchungen zur Hydratisierungsdynamik und Löslichkeit methylierter Cyclodextrine mittels Röntgenkristallographic und Neutronenstreuung

Cover I Abstract in German V Abstract in English VI Acknowledgements VII Contents IX List of figures XIII List of tables XV Acronyms XVII 1\. Introduction 1 1.1 Cyclodextrins 1 1.2 Methylated cyclodextrins 20 2\. Materials and methods 33 2.1 Materials 33 2.2 X-ray crystallographic method 33 2.3 Neutron scattering method 42 3\. Results and discussion 51 3.1 X-ray crystallographic study 51 3.2 Neutron scattering study 78 4\. Conclusions 89 Bibliography 93 A. Crystallographic supporting information 107 B. Neutron scattering supporting information 121 Curriculum vitae 127In this study, X-ray crystallographic and neutron scattering experiments have been performed in order to comprehend the negative solubility coefficient in water of methylated cyclodextrins (CDs). X-ray analyses have been carried out for two crystal forms of both heptakis(2,6-di-O-methyl)-beta-CD (DIMEB) and octakis(2,3,6-tri-O-methyl)-gamma-CD (TRIMEG) which were grown from cold water at 291 K, and neutron scattering measurements for aqueous solutions of DIMEB, TRIMEG, and gamma-CD at 287-323 K. In DIMEB.2H2O and DIMEB.15H2O, the DIMEB molecules adopt ``round'' conformations stabilized by interglucose O3(n)-H...O2(n \+ 1) hydrogen bonds. While the former has 2 water molecules, one being included in the cavity and one in the intermolecular space, the latter has 15 water molecules which are all located outside the cavity and form a channel clathrate hydrate host structure enclosing the guest DIMEB. The abundance of 15 host-guest hydrogen bond interactions give rise to high thermal stability of the DIMEB.15H2O crystal. (4TRIMEG).19.3H2O and TRIMEG.4.5H2O which have no interglucose O3(n)-H...O2(n \+ 1) hydrogen bonds (because all O-H groups are methylated) are more flexible and the molecular structure of TRIMEG is notably different. In (4TRIMEG).19.3H2O, all four TRIMEG molecules adopt ``elliptical'' conformations with two diametrically opposed glucose units 1 and 5 flipped by ca. 180o (anti orientation). The 19.3 water molecules are distributed over 27 positions both inside and outside the TRIMEG cavities and are hydrogen bonded in different patterns to the four TRIMEG molecules. This contrasts TRIMEG.4.5H2O in which the molecular structure is ``round'' with all glucoses orientated syn and the 4.5 water molecules are accommodated in its cavity. The highly hydrated crystal forms of DIMEB.15H2O, (4TRIMEG).19.3H2O, and TRIMEG.4.5H2O grown from cold water indicate that the hydration may be associated with the high solubility of these methylated CDs in cold water. This is evidenced by neutron scattering results showing that in aqueous solution at 287 K, DIMEB and TRIMEG are hydrated by a large number of water molecules and diffuse slowly as indicated by a broad quasielastic peak which is characteristic of diffusive motion in the liquid state. As the temperature rises to 305 K, the hydration number decreases, DIMEB and TRIMEG diffuse faster. When the temperarure reaches the crystallization point at 323 K, the hydration number decreases rapidly, DIMEB aggregates and crystallizes as shown by a sharp elastic peak which indicates very slow motion of larger, solid state particles. For comparison, for gamma-CD (with normal solubility behavior), the diffusion mobility increases with increasing temperature and the hydration number decreases and converges to an asymptotic value at higher temperature.Im Rahmen der vorliegenden Arbeit wurde die strukturelle Ursache für die abnehmende Löslichkeit von methylierten Cyclodextrinen (CD) in Wasser mit steigender Temperatur untersucht. Mittels Röntgenstrukturanalyse wurden zwei aus kalten Wasser Kristallisierten, hydratisierte Formen und wäßrige Lösungen von Heptakis-(2,6-di-O-methyl)-beta-CD (DIMEB), Octakis-(2,3,6-tri-O-methyl )-gamma-CD (TRIMEG) und nicht methyliertem gamma-CD mit Neutronenstreuung bei 287-323 K untersucht der beiden DIMEB und TRIMEG analysiert. Im Fall zweier Kristallformen von DIMEB mit jeweils 2 und 15 Kristallwassern besitzt das CD eine ,,runde'' Konformation, die durch Wasserstoffbrücken O3(n)-H...O2(n \+ 1) stabilisiert wird. Während in der ersten Kristallform sich eines der beiden Wassermoleküle im Kanal und das andere zwischen CD- Molekülen befindet, sind in der zweiten Kristallform alle 15 Wassermoleküle außerhalb des Kanals koordinert und bilden eine Clathrat-Hydratstruktur, die jeweils ein DIMEB Molekül einschließt. Die große Anzahl an Wasserstoffbrücken innerhalb dieser Hydratstuktur bewirkt eine realtiv hohe thermische Stabilität der DIMEB.15H2O Kristalle. In den zwei untersuchten Kristallformen des voll methylierten TRIMEG, (4TRIMEG).19,3H2O und TRIMEG.4,5H2O, können keine O3(n)-H...O2(n \+ 1) Wasserstoffbrücken ausgebildet werden, wodurch die CD flexibler sind und die TRIMEG Moleküle in einer anderen Konformation vorliegen können. Im Fall des (4TRIMEG).19,3H2O nehmen die vier CD eine ,,elliptische'' Konformation an und die diametral gegenüberliegenden Glukoseeinheiten 1 und 5 sind 180o verdreht (anti Orientierung). Die 19,3 Wassermoleküle befinden sich an 27 Positionen innerhalb und außerhalb der TRIMEG Kanäle und bilden in den vier TRIMEG Molekülen unterschiedliche Wasserstoffbrückenmuster. Im Gegensatz dazu zeigt das TRIMEG Moleküls in der zweite Kristallform eine ,,runde'' Konformation mit allen Glukosebausteinen in der syn Form. In dieser Kristallform sind alle 4,5 Wassermolüle im TRIMEG-Kanal lokalisiert. Die mit einer großen Anzahl an Wassermolekülen erhaltenen Kristallformen DIMEB.15H2O, (4TRIMEG).19,3H2O und TRIMEG.4,5H2O wurden aus kaltem Wasser kristallisiert während DIMEB und TRIMEG bei 333 K nur als Di- oder Anhydrate kristallisieren. Die Hydratisierung ist damit eine Erklärung für die gute Löslichkeit der methylierten CD. Der Einfluß der Hydratisierung der beiden CD DIMEB und TRIMEG auf ihre Kristallisation konnte mittels Neutronenstreuung bestätigt werden. So sind bei einer Temperatur von 287 K beide CD durch eine große Anzahl an Wassermolekülen koordiniert. Aufgrund dieser umfangreichen Hydratation ist die Diffusion der CD Molküle gering. Bei zunehmender Temperatur nimmt die Hydratation ab und die Diffusion zu. Die Hydratationsabnahme zeigt im Fall von DIMEB bei 323 K, der Kristallisationtemperatur, einen drastischen Verlauf. Bei dieser Temperatur ist die Diffusion sehr gering und entspricht der Bewegung kleiner Partikel (Mikrokristalle). Im Vergleich dazu besitzt das nicht methylierte gamma-CD ein normales Löslichkeitsverhalten. Mit zunehmender Temperatur nehmen zwar auch die Mobilität zu und die Hydratation ab, aber letztere konvergiert bei hoher Temperatur zu einem Wert, der eine gute Löslichkeit gewährleistet

Distinctive Supramolecular Features of β-Cyclodextrin Inclusion Complexes with Antidepressants Protriptyline and Maprotiline: A Comprehensive Structural Investigation

Depression, a global mental illness, is worsened due to the coronavirus disease 2019 (COVID-2019) pandemic. Tricyclic antidepressants (TCAs) are efficacious for the treatment of depression, even though they have more side effects. Cyclodextrins (CDs) are powerful encapsulating agents for improving molecular stability, water solubility, and lessening the undesired effects of drugs. Because the atomic-level understanding of the β-CD–TCA inclusion complexes remains elusive, we carried out a comprehensive structural study via single-crystal X-ray diffraction and density functional theory (DFT) full-geometry optimization. Here, we focus on two complexes lining on the opposite side of the β-CD–TCA stability spectrum based on binding constants (Kas) in solution, β-CD–protriptyline (PRT) 1—most stable and β-CD–maprotiline (MPL) 2—least stable. X-ray crystallography unveiled that in the β-CD cavity, the PRT B-ring and MPL A-ring are aligned at a nearly perfect right angle against the O4 plane and primarily maintained in position by intermolecular C–H···π interactions. The increased rigidity of the tricyclic cores is arising from the PRT -CH=CH- bridge widens, and the MPL -CH2–CH2- flexure narrows the butterfly angles, facilitating the deepest and shallower insertions of PRT B-ring (1) and MPL A-ring (2) in the distorted round β-CD cavity for better complexation. This is indicated by the DFT-derived complex stabilization energies (ΔEstbs), although the complex stability orders based on Kas and ΔEstbs are different. The dispersion and the basis set superposition error (BSSE) corrections were considered to improve the DFT results. Plus, the distinctive 3D arrangements of 1 and 2 are discussed. This work provides the first crystallographic evidence of PRT and MPL stabilized in the β-CD cavity, suggesting the potential application of CDs for efficient drug delivery

Inclusion Scenarios and Conformational Flexibility of the SSRI Paroxetine as Perceived from Polymorphism of β-Cyclodextrin–Paroxetine Complex

Depression, a global mental health problem, is prevalent during the coronavirus disease 2019 (COVID-19) pandemic and can be efficiently treated by selective serotonin reuptake inhibitors (SSRIs). Our study series aims at forwarding insights on the β-cyclodextrin (β-CD)–SSRI inclusion complexes by X-ray crystallography combined with density functional theory (DFT) calculation. Here, we report a new crystal form (II) of the 1:1 β-CD–paroxetine (PXT) complex, which is inspired by the reported 2:1 β-CD–PXT complex (crystal form I), reflecting an elusive phenomenon of the polymorphism in CD inclusion complexes. The β-CD–PXT polymorphism stems from the PXT conformational flexibility, which is defined by torsion angles κ, ε around the -CH2–O- group bridging the A- and C–D-rings, of which those of PXT in I and II are totally different. While PXT (II) in an open V-shaped conformation that has the B-ring shallowly inserted in the β-CD cavity, PXT (I) in a closed U-shaped structure is mostly entirely embedded in the β-CD dimeric cavity, of which the A-ring is deeply inserted in the main β-CD cavity. However, PXT molecules in both crystal forms are similarly maintained in the CD cavity via host–guest N–H···O5/O6 H-bonds and C/O–H···π(B/C) interactions and β-CDs have similar 3D arrangements, channel (II) vs. screw-channel (I). Further theoretical explorations on the β-CD–PXT thermodynamic stabilities and the PXT conformational stabilities based on their potential energy surfaces (PESs) have been completed by DFT calculations. The 2:1 β-CD–PXT complex with the greater presence of dispersion interactions is more energetically favorable than the unimolar complex. Conversely, whereas free PXT, PXT (II) and PXT in complex with serotonin transporter are more energetically stable, PXT (I) is least stable and stabilized in the β-CD cavity. As SSRIs could lessen the COVID-19 severity, the CD inclusion complexation not only helps to improve the drug bioavailability, but also promotes the use of antidepressants and COVID-19 medicines concurrently

Identification of highly potent α-glucosidase inhibitory and antioxidant constituents from Zizyphus rugosa bark: enzyme kinetic and molecular docking studies with active metabolites

Context: Previous studies have shown that extracts of Zizyphus rugosa Lam. (Rhamnaceae) bark contained phytoconstituents with antidiabetic potential to lower blood glucose levels in diabetic rats. However, there has been no report on the active compounds in this plant as potential antidiabetic inhibitors. Objective: We evaluated the α-glucosidase inhibitory and antioxidant activities of Z. rugosa extract. Moreover, the active phytochemical constituents were isolated and characterized. Materials and methods: The α-glucosidase inhibition of crude ethanol extract obtained from the bark of Z. rugosa was assayed as well as the antioxidant activity. Active compounds (1–6) were isolated, the structures were determined, and derivatives (2a–2 l) were prepared. All compounds were tested for their α-glucosidase inhibitory (yeast and rat intestine) and antioxidant (DPPH) activities. Results: The active α-glucosidase inhibitors (1–6) were isolated from Z. rugosa bark and 12 derivatives (2a–2 l) were prepared. Compound 2 showed the most powerful yeast α-glucosidase inhibitory activity (IC50 16.3 μM), while compounds 3 and 4 display only weak inhibition toward rat intestinal α-glucosidase. Moreover, compound 6 showed the most potent antioxidant activity (IC50 42.8 μM). The molecular docking results highlighted the role of the carboxyl moiety of 2 for yeast α-glucosidase inhibition through H-bonding. Discussion and conclusions: These results suggest the potential of Z. rugosa bark for future application in the treatment of diabetes and active compounds 1 and 2 have emerged as promising molecules for therapy