Structural studies of analgesics and their interactions. XII. Structure and interactions of anti-inflammatory fenamates. A concerted crystallographic and theoretical conformational study

A theoretical conformational analysis of fenamates, which are N-arylated derivatives of anthranilic acid or 2-aminonicotinic acid with different substituents on the aryl (phenyl) group, is reported. The analysis of these analgesics, which are believed to act through the inhibition of prostaglandin biosynthesis, was carried out using semi-empirical potential functions. The results and available crystallographic observations have been critically examined in terms of their relevance to drug action. Crystallographic studies of these drugs and their complexes have revealed that the fenamate molecules share a striking invariant feature, namely, the sixmembered ring bearing the carboxyl group is coplanar with the carboxyl group and the bridging imino group,the coplanarity being stabilized by resonance interactions and an internal hydrogen bond between the imino and carboxyl groups. The results of the theoretical analysis provide a conformational rationale for the observed invariant coplanarity. The second sixmembered ring, which provides hydrophobicity in a substantial part of the molecule, has limited conformational flexibility in meclofenamic, mefenamic and flufenamic acids. Comparison of the conformational energy maps of these acids shows that they could all assume the same conformation when bound to the relevant enzyme. The present study provides a structural explanation for the difference in the activity of niflumic acid, which can assume a conformation in which the whole molecule is nearly planar. The main role of the carboxyl group appears to be to provide a site for intermolecular interactions in addition to helping in stabilizing the invariant coplanar feature and providing hydrophilicity at one end of the molecule. The fenamates thus provide a good example of conformation- dependent molecular asymmetry.

5-Benzyl-1-(4-fluorophenyl)-2-phenyl-4,5,6,7-tetrahydro-1H-pyrrolo3,2 -c] pyridine

In the title compound, C26H23FN2, the dihedral angle between the 4-fluorophenyl ring and the adjacent phenyl ring is 62.3 (1)degrees. The crystal structure is stabilized by C-H center dot center dot center dot pi interactions.

Structure of 2',3'-O-isopropylideneguanosine dimethylsulfoxide solvate

CI3H17N5Os.C2H6OS, Mr=401.23, orthorhombic,P21212 p grown from Me2SO, a = 10.749 (2),b = 13.219 (2), c = 14.056 (2) A, V= 1997-23 A 3, Z =4, D_=1.40, D x=l.335Mgm -3, 2(CuKa)= 1.5418/~', g = 1.694 mm -~, F(000) = 848.00, T=293K, R =0.0538, wR =0.0634 for 2105 unique reflections with F > 3o(F). The asymmetric unit contains one nucleoside molecule with a disordered solvent Me2S_O molecule. The geometry about the C(4')-C(5') bond is gauche-gauche. The guanosine base is in the anti conformation with the furanose ring having C(3')-exo (E 3) puckering. The bases do not show any stacking in contrast to other guanosine-containing structures. The crystal structure is stabilized by N--H...N and N--H...O hydrogen bonding.

Structure of 6-acetoxycoumarin: topochemical photodimerization and analysis of acetoxy...acetoxy interactions in the solid state

C~HaO 4, Mr=204.2, monoclinic, P2Jn,a=3.900(1), =37.530(6), c=6.460(1)A, fl=103.7 (1) °, V= 918.5 (5) A 3, Z = 4, D m = 1.443, D x --- 1.476 Mg m -3, Cu Ks, 2 = 1.5418 ,/k, /t = 0.86 mm -~, F(000) = 424, T= 293 K, R = 0.075 for 1019 significant reflections. Molecules pack in fl-type stacking mode which is characterized by the close packing of parallel and nearly planar reactive double bonds with a separation of 3.900/~ along the a axis.The syn head-head dimer obtained is the direct consequence of this packing arrangement. Molecular packing is stabilized by intermolecular C-H...O hydrogen bonding. Analysis of acetoxy...acetoxy interactions in the acetoxy compounds retrieved from the Cambridge Structural Database reveal that the majority of them are anti-dipolar.

Structure of L-tyrosyl-L-leucine monohydrate

C15H22N204.H20 , Mr= 312.37, monoclinic,P21, a=5.577(2), b=8.686(2), c= 16.228 (2) A,fl=92.63(2) ° , V=785(1)A 3, Z=2, O =1.34,Dx= 1.32Mgm -3, CuKa, 2= 1.54184'~, /2=0.78 mm -I, F(000) = 320, T= 293 K. The final R value for 1607 observed reflections ll,,>_3tr(l,,)l is 0.039. The terminal N 1 is protonated and the dipeptide exists as a zwitterion. The crystal structure is stabilized by extensive hydrogen-bonding interactions involving N and O atoms, with N...O in the range 2.65 (1)-2.95 (1) ,/~ and O...O in the range 2.60 (1)-2.78 (1) A.

Structure of L-Arginyl-L-aspartie Acid Dihydrate

C~0H~gN5Os.2H20, Mr=325.32, monoclinic,P2~, a = 12.029 (2), b=4.904 (2), c=13.215 (2) A, fl= 107.68 (2) ° , F= 743 (1) A 3, Z= 2,D m = 1-45, D x = 1.45 Mg m -3, Cu Ka, 2 = 1.54184 A,fl= 1.01mm -1, F(000)=348, T=293K. The final R value for 1277 observed reflections 110 >_ 3tr(Io)l is 0.031. The dipeptide exists as a zwitterion. The arginyl side-chain conformation is similar to that found in arginyl-glutamic acid [Pandit, Seshadri & Viswamitra (1983). Acta Cryst. C39, 1669-16721. The guanidyl group forms a pair of hydrogen bonds with oxygen atoms of the backbone carboxyl group. The crystal structure is also stabilized by -bonding interactions involving both water molecules.

Structure of N2-carbamoyl-L-asparagine

CsH9N304, M r= 175.1, orthorhombic,P212~2 ~, a = 7.486 (1), b = 9.919 (2), c =20.279 (2) A, V= 1505.8 A 3, z = 8, D x = 1.54, D m = 1.60 Mg m -3, ~,(Cu Ka) = 1.5418 A, g = 1. I I mm -~, F(000) = 736, T = 300 K, final R = 0.032 for 1345 observed reflections. The two independent molecules in the asymmetric unit are related by a pseudo twofold axis, with the asparagine side chains having different conformations [X 2 being -132.1 (3) and 139.6 (2)°]. The crystal structure is stabilized by extensive hydrogen bonding, with a specific interaction between the carboxyl group of one molecule and the carbamoyl group of another forming hydrogen-bonded chains.

Synthetic peptide models for the redox-active disulfide loop of glutaredoxin. Conformational studies

Two cyclic peptide disulfides Boc-Cys-Pro-X-Cys-NHMe (X = L-Tyr or L-Phe) have been synthesized as models for the 14-membered redox-active disulfide loop of glutaredoxin. 'H NMR studies at 270 MHz in chloroform solutions establish a type I 0-turn conformation for the Pro-X segment in both peptides, stabilized by a 4-1 hydrogen bond between the Cys(1) CO and Cys(4) NH groups. Nuclear Overhauser effects establish that the aromatic ring in the X = Phe peptide is oriented over the central peptide unit. In dimethyl sulfoxide solutions two conformational species are observed in slow exchange on the NMR time scale, for both peptides. These are assigned to type I and type I1 p-turn structures with -Pro-Tyr(Phe)-as the corner residues. The structural assignments are based on correlation of NMR parameters with model 14-membered cyclic cystine peptides with Pro-X spacers. Circular dichroism studies based on the -S-Sn- u* transition suggest a structural change in the disulfide bridge with changing solvent polarity, establishing conformational coupling between the peptide backbone and the disulfide linkage in these systems.

A Comparative Study of Liapunov Stability Analyses of Flexible Damped Satellites

A literal Liapunov stability analysis of a spacecraft with flexible appendages often requires a division of the associated dynamic potential into as many dependent parts as the number of appendages. First part of this paper exposes the stringency in the stability criteria introduced by such a division and shows it to be removable by a “reunion policy.” The policy enjoins the analyst to piece together the sets of criteria for each part. Employing reunion the paper then compares four methods of the Liapunov stability analysis of hybrid dynamical systems illustrated by an inertially coupled, damped, gravity stabilized, elastic spacecraft with four gravity booms having tip masses and a damper rod, all skewed to the orbital plane. The four methods are the method of test density function, assumed modes, and two and one-integral coordinates. Superiority of one-integral coordinate approach is established here. The design plots demonstrate how elastic effects delimit the satellite boom length.

Tl1-xPbxCaSr2Cu2O7: Another 1122 high-Tc superconductor

The 1122 member of the Tl(Ca, Sr)n+1CunO2n+3 system is stabilized by partial substitution of Tl by Pb. Tl1?xPbxCaSr2Cu2O7 with x=0.25 and 0.5 have both primitive tetragonal structures (c 12.1 Å) showing onset of superconductivity around 70 K and 90 K, respectively.

Crystal Structure of Staphylococcus aureus Metallopeptidase (Sapep) Reveals Large Domain Motions between the Manganese-bound and Apo-states

Proteases belonging to the M20 family are characterized by diverse substrate specificity and participate in several metabolic pathways. The Staphylococcus aureus metallopeptidase, Sapep, is a member of the aminoacylase-I/M20 protein family. This protein is a Mn2+-dependent dipeptidase. The crystal structure of this protein in the Mn2+-bound form and in the open, metal-free state suggests that large interdomain movements could potentially regulate the activity of this enzyme. We note that the extended inactive conformation is stabilized by a disulfide bond in the vicinity of the active site. Although these cysteines, Cys(155) and Cys(178), are not active site residues, the reduced form of this enzyme is substantially more active as a dipeptidase. These findings acquire further relevance given a recent observation that this enzyme is only active in methicillin-resistant S. aureus. The structural and biochemical features of this enzyme provide a template for the design of novel methicillin-resistant S. aureus-specific therapeutics.

Methylene blue sensitized dichromated gelatin holograms: a study of their storage life and reprocessibility

The results of an experimental investigation on the storage life and reprocessibility of methylene blue sensitized dichromated gelatin (MBDCG) holograms are reported. The major conclusions of the investigation are: (i) Storage of MBDCG holograms in normal laboratory conditions for long periods is possible and it diminishes somewhat their diffraction efficiency. (ii) The results on short time storage and long time storage are almost similar, thus indicating that the diffraction efficiency can be stabilized through storage in a relatively short period of time. (iii) The deterioration in the diffraction efficiency on storage is less [D(eta) < 20%] for gratings of low/medium initial efficiency (eta < 70%) and it is more for gratings of high initial efficiency. (iv) About 65-95% restoration of the diffraction efficiency can be accomplished through reprocessing. (v) The restoration of diffraction efficiency is almost perfect [R(eta) > 80%] for gratings of low/medium initial efficiency (eta <75%) whereas it is rather imperfect for gratings having high initial efficiency.

Polymeereillä stabiloitu amorfinen formulaatio

Nowadays growing number of new active pharmaceutical ingredients (API) have large molecular weight and are hydrophobic. The energy of their crystal lattice is bigger and polarity has decreased. This leads to weakened solubility and dissolution rate of the drug. These properties can be enhanced for example by amorphization. Amorphous form has the best dissolution rate in the solid state. In the amorphous form drug molecules are randomly arranged, so the energy required to dissolve molecules is lower compared to the crystalline counterpart. The disadvantage of amorphous form is that it is unstable. Amorphous form tends to crystallize. Stability of amorphous form can be enhanced by adding an adjuvant to drug product. Adjuvant is usually a polymer. Polymers prevent crystallization both by forming bonds with API molecules and by steric hindrance. The key thing in stabilizing amorphous form is good miscibility between API and polymer. They have to be mixed in a molecular level so that the polymer is able to prevent crystallization. The aim of this work was to study miscibility of drug and polymer and stability of their dispersion with different analytical methods. Amorphous dispersions were made by rotary evaporator and freeze dryer. Amorphicity was confirmed with X-ray powder diffraction (XRPD) right after preparation. Itraconazole and theophylline were the chosen molecules to be stabilized. Itraconazole was expected to be easier and theophylline more difficult to stabilize. Itraconazole was stabilized with HPMC and theophylline was stabilized with PVP. Miscibility was studied with XRPD and differential scanning calorimetry (DSC). In addition it was studied with polarized light microscope if miscibility was possible to see visually. Dispersions were kept in stressed conditions and the crystallization was analyzed with XRPD. Stability was also examined with isothermal microcalorimetry (IMC). The dispersion of itraconazole and theophylline 40/60 (w/w) was completely miscible. It was proved by linear combination of XRPD results and single glass transition temperature in DSC. Homogenic well mixed film was observed with light microscope. Phase separation was observed with other compositions. Dispersions of theophylline and PVP mixed only partly. Stability of itraconazole dispersions were better than theophylline dispersions which were mixed poorer. So miscibility was important thing considering stability. The results from isothermal microcalorimetry were similar to results from conventional stability studies. Complementary analytical methods should be used when studying miscibility so that the results are more reliable. Light microscope is one method in addition to mostly used XRPD and DSC. Analyzing light microscope photos is quite subjective but it gives an idea of miscibility. Isothermal microcalorimetry can be one option for conventional stability studies. If right conditions can be made where the crystallization is not too fast, it may be possible to predict stability with isothermal microcalorimetry.

Mechanical Anisotropy in Crystalline Saccharin: Nanoindentation Studies

The nanoindentation technique has been employed to relate the mechanical properties of saccharin single crystals with their internal structure. Indentations were performed on (100) and (011) faces to assess the mechanical anisotropy. The load-displacement (P-h) curves indicate significant differences in the nature of the plastic deformation on the two faces. The P-h curves obtained on the (011) plane are smooth, reflecting homogeneous plasticity. However, displacement bursts (pop-ins) are observed in the P-h curves obtained on the (100) plane suggesting a discrete deformation mechanism. Marginal differences exist in the hardness and modulus on the two faces that may, in part, be rationalized, although one notes that saccharin has a largely three-dimensional close-packed structure. The structural origins of the fundamentally different deformation mechanisms on (100) and (011) are discussed in terms of the dimensionality of the hydrogen bonding networks. Down the (100) planes, the saccharin dimers are stacked and are stabilized by nonspecific van der Wants interactions mostly between aromatic rings. However, down the (011) planes, the molecules are stabilized by more directional and cross-linked C-H ... O hydrogen bonds. This anisotropy in crystal packing and interactions is reflected in the mechanical behavior on these faces. The displacements associated with the pop-ins were found to he integral multiples oldie molecule separation distances. Nanoindentation offers an opportunity to compare experimentally, and in a quantitative way, the various intermolecular interactions that fire present in a molecular crystal.

N-2-(4-Methyl-2-quinolyl)phenyl]acetamide: a P1 structure with Z=4

The title compound, C18H16N2O, crystallizes in the triclinic space group P1, with four independent molecules in the asymmetric unit wherein two molecules have an irregular -ac, -ac, +ap conformation (ap, antiperiplanar; ac, anticlinal), while the other molecules exhibit a different, +ac, +ac, +ap conformation. The planar (r.m.s. deviation = 0.006 A in each of the four molecules) quinoline ring systems of the four molecules are oriented at dihedral angles of 32.8 (2), 33.4 (2), 31.7 (2) and 32.3 (2)degrees with respect to the benzene rings. Intramolecular N-H...N interactions occur in all four independent molecules. The crystal packing is stabilized by intermolecular N-H...O and C-H...O hydrogen bonds, and are further consolidated by C-H...pi and pi-pi stacking interactions centroid-centroid distances = 3.728 (3), 3.722 (3), 3.758 (3) and 3.705 (3) A].