Crystal structure, quantum chemical insights, and molecular docking studies of Naryl-2-(N-disubstituted) acetamide compounds: potential inhibitors for neurodegenerative enzymes.

The increase in and concern about neurodegenerative diseases continue to grow in an increasingly long-lived world population. Therefore, the search for new drugs continues to be a priority for medicinal chemistry. We present here the synthesis of a series of compounds with acetamide nuclei. Their structures were established using UV-Visible, NMR, HRMS and IR techniques. Furthermore, we report the crystal structures that were obtained from compounds 5a-5d by X-ray diffraction. The compounds were evaluated as potential inhibitors of the monoxidase enzymes; A (MAO-A) and B (MAO-B), and cholinesterases; acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) through in silico studies using the induced fit docking (IFD) method and binding free energy (ΔGbind) calculations by the MMGBSA method. Interestingly, compounds 5b, 5c and 5d showed much better ΔGbind than the reference drug Zonisamide. Compound 5c is the best in the series, which indicates a potential selective affinity of our compounds against MAO-B, which could be a promising finding in the search for new drugs for Parkinson's disease treatment. The acetamide crystal exhibits moderate NLO properties suggesting that it could be considered a potential candidate for application in nonlinear optical devices.

The Methylene Spacer Matters: The Structural and Luminescent Effects of Positional Isomerism of n-Methylpyridyltriazole Carboxylate Semi-Rigid Ligands in the Structure of Zn(II) Based Coordination Polymers.

Two Zn(II) coordination polymers (CPs) based on n-methylpyridyltriazole carboxylate semi-rigid organic ligands (n-MPTC), with n = 3 (L1) and 4 (L2), have been prepared at the water n-butanol interphase by reacting Zn(NO3)2·4H2O with NaL1 and NaL2. This allows us to systematically investigate the influence of the isomeric positional effect on their structures. The organic ligands were obtained by saponification from their respective ester precursors ethyl-5-methyl-1-(pyridin-3-ylmethyl)-1H-1,2,3-triazole-4-carboxylate (P1) and ethyl-5-methyl-1-(pyridin-4-ylmethyl)-1H-1,2,3-triazole-4-carboxylate (P2), resulting in their corresponding sodium salt forms, 3-MPTC, and 4-MPTC. The structure of the Zn(II) CPs determined by single-crystal X-ray diffraction reveals that both CPs have 2D supramolecular hydrogen bond networks. The 2D supramolecular network of [Zn(L1)]n (1) is built up by hydrogen bond interactions between oxygen and hydrogen atoms between neighboring n-methylpyridyltriazole molecules, whereas in [Zn(L2)·4H2O]n (2) the water molecules link 1D polymeric chains forming a 2D supramolecular aggregate. The structures of 1 and 2 clearly show that the isomeric effect in the semi-rigid ligands plays a vital role in constructing the Zn(II) coordination polymers, helped by the presence of the methylene spacer group, in the final structural conformation. The structures of 1 and 2 significantly affect their luminescent properties. Thus, while 2 shows strong emission at room temperature centered at 367 nm, the emission of 1 is quenched substantially.

4-Carboxypiperidinium 1-carboxycyclobutane-1-carboxylate.

The title salt, C(6)H(12)NO(2)(+)·C(6)H(7)O(4)(-) or ISO(+)·CBDC(-), is an ionic ensemble assisted by hydrogen bonds. The amino acid moiety (ISO or piperidine-4-carboxylic acid) has a protonated ring N atom (ISO(+) or 4-carboxypiperidinium), while the semi-protonated acid (CBDC(-) or 1-carboxycyclobutane-1-carboxylate) has the negative charge residing on one carboxylate group, leaving the other as a neutral -COOH group. The -(+)NH(2)- state of protonation allows the formation of a two-dimensional crystal packing consisting of zigzag layers stacked along a separated by van der Waals distances. The layers extend in the bc plane connected by a complex network of N-H···O and O-H···O hydrogen bonds. Wave-like ribbons, constructed from ISO(+) and CBDC(-) units and described by the graph-set symbols C(3)(3)(10) and R(3)(3)(14), run alternately in opposite directions along c. Intercalated between the ribbons are ISO(+) cations linked by hydrogen bonds, forming rings described by the graph-set symbols R(6)(6)(30) and R(4)(2)(18). A detailed analysis of the structures of the individual components and the intricate hydrogen-bond network of the crystal structure is given.

Two conformational polymorphs of 4-methylhippuric acid.

4-Methylhippuric acid {systematic name: 2-[(4-methylbenzoyl)amino]ethanoic acid}, a p-xylene excreted metabolite with a backbone containing three rotatable bonds (R-bonds), is likely to produce more than one stable molecular structure in the solid state. In this work, we prepared polymorph I by slow solvent evaporation (plates with Z' = 1) and polymorph II by mechanical grinding (plates with Z' = 2). Potential energy surface (PES) analysis, rotating the molecule about the C-C-N-C torsion angle, shows four conformational energy basins. The second basin, with torsion angles near -73°, agree with the conformations adopted by polymorph I and molecules A of polymorph II, and the third basin at 57° matched molecules B of polymorph II. The energy barrier between these basins is 27.5 kJ mol-1. Superposition of the molecules of polymorphs I and II rendered a maximum r.m.s. deviation of 0.398 Å. Polymorphs I and II are therefore true conformational polymorphs. The crystal packing of polymorph I consists of C(5) chains linked by N-H...O interactions along the a axis and C(7) chains linked by O-H...O interactions along the b axis. In polymorph II, two molecules (A with A or B with B) are connected by two acid-amide O-H...O interactions rendering R22(14) centrosymmetric dimers. These dimers alternate to pile up along the b axis linked by N-H...O interactions. A Hirshfeld surface analysis localized weaker noncovalent interactions, C-H...O and C-H...π, with contact distances close to the sum of the van der Waals radii. Electron density at a local level using the Quantum Theory of Atoms in Molecules (QTAIM) and the Electron Localization Function (ELF), or a semi-local level using noncovalent interactions, was used to rank interactions. Strong closed shell interactions in classical O-H...O and N-H...O hydrogen bonds have electron density highly localized on bond critical points. Weaker delocalized electron density is seen around the p-methylphenyl rings associated with dispersive C-H...π and H...H interactions.

Structure and conformational analysis of a bidentate pro-ligand, C21H34N2S2, from powder synchrotron diffraction data and solid-state DFTB calculations.

The molecular and crystalline structure of ethyl 1',2',3',4',4a',5',6',7'-octahydrodispiro[cyclohexane-1,2'-quinazoline-4',1''-cyclohexane]-8'-carbodithioate (I) was solved and refined from powder synchrotron X-ray diffraction data. The initial model for the structural solution in direct space using the simulated annealing algorithm implemented in DASH [David et al. (2006). J. Appl. Cryst. 39, 910-915] was obtained performing a conformational study on the fused six-membered rings of the octahydroquinazoline system and the two spiran cyclohexane rings of (I). The best model was chosen using experimental evidence from 1H and 13C NMR [Contreras et al. (2001). J. Heterocycl. Chem. 38, 1223-1225] in combination with semi-empirical AM1 calculations. In the refined structure the two spiran rings have the chair conformation, while both of the fused rings in the octahydroquinazoline system have half-chair conformations compared with in-vacuum density-functional theory (DFT) B3LYP/6-311G*, DFTB (density-functional tight-binding) theoretical calculations in the solid state and other related structures from X-ray diffraction data. Compound (I) presents weak intramolecular hydrogen bonds of the type N-H...S and C-H...S, which produce delocalization of the electron density in the generated rings described by graph symbols S(6) and S(5). Packing of the molecules is dominated by van der Waals interactions.

Molecular and crystalline structures of three (S)-4-alkoxycarbonyl-2-azetidinones containing long alkyl side chains from synchrotron X-ray powder diffraction data.

The (S)-4-alkoxo-2-azetidinecarboxylic acids are optically active beta-lactam derivatives of aspartic acid, which are used as precursors of carbapenem-type antibiotics and poly-beta-aspartates. The crystal structures of three (S)-4-alkoxo-2-azetidinecarboxylic acids with alkyl chains with 10, 12 and 16 C atoms were solved using parallel tempering and refined against the X-ray powder diffraction data using the Rietveld method. The azetidinone rings in the three compounds display a pattern of asymmetrical bond distances and an almost planar conformation; these characteristics are compared with periodic solid-state, gas-phase density-functional theory (DFT) calculations and MOGUL average bond distances and angles from the CSD. The compounds pack along [001] as corrugated sheets separated by approximately 4.40 A and connected by hydrogen bonds of the type N-H...O.

Redetermination of 1-carboxy-cyclo-hexan-1-aminium chloride.

The crystal structure of the title compound, C(7)H(14)NO(2) (+)·Cl(-), was reported previously [Chacko, Srinivasan & Zand (1975 ▶). J. Cryst. Mol. Struct.5, 353-357] from Weissenberg photographic data with R = 0.113. It has now been redetermined, providing a significant increase in the precision of the derived geometric parameters, viz. mean σ(C-C) = 0.003 Šin the present work compared with 0.021 Šfor the previous work. The complete cation is generated by crystallographic mirrror symmetry, with three C atoms, two O atoms and the N atom lying on the reflecting plane; the chloride anion also has m site symmetry. The crystal structure is established by a two-dimensional network of O-H⋯Cl and N-H⋯Cl hydrogen bonds, generating C(1) (2)(4) and C(1) (2)(7) chains, and R(2) (4)(8) and R(2) (4)(14) rings.

rac-1-Acetyl-5-benzyl-2-thioxoimidazolidin-4-one.

In the title compound, C(12)H(12)N(2)O(2)S, the mol-ecules have a wing-like conformation, with a distance of 3.797 (2) Šbetween the centroids of the five- and six-membered rings. In the crystal structure, mol-ecules are linked by N-H⋯O hydrogen bonds, forming infinite one-dimensional zigzag chains, running along [001], with a C(4) graph-set motif.

Non-covalent interactions in the multicomponent crystal of 1-aminocyclopentane carboxylic acid, oxalic acid and water: a crystallographic and a theoretical approach.

Single-crystal X-ray diffraction and quantum mechanical theories were used to examine in detail the subtle nature of non-covalent interactions in the [2:1:1] multicomponent crystal of 1,1-aminocyclopentanecarboxylic acid:oxalic acid:water. The crystal, which is a hydrate salt of the amino acid with the hydrogen-oxalate ion, also contains the zwitterion of the amino acid in equal proportions. It was found that a dimeric cation [Acc5(Z)...Acc5(C)]+ bonded by an O-H...O hydrogen bond exists due to a charge transfer between acid and carboxylate groups. The three-dimensional crystal is built by blocks stacked along the [101] direction by dispersion interactions, with each block growing along two directions: a hydrogen oxalate HOX-...HOX- catameric supramolecular structure along the [010] direction; and double ...HOX--W-[Acc5(Z)... Acc5(C)]+... chains related by inversion centers along the [1 0 {\bar 1}] direction. A PBE-DFT optimization, under periodic boundary conditions, was carried out. The fully optimized structure obtained was used to extract the coordinates to calculate the stabilization energy between the dimers under the crystal field, employing the M062X/aug-cc-pVTZ level of theory. The non-covalent index isosurfaces employed here allow the visualization of where the hydrogen bond and dispersion interactions contribute within the crystal. The crystal atomic arrangements are analyzed by employing the Atoms in Molecules and electron localization function theories. Within this context, the presence of density bond critical points is employed as a criterion for proving the existence of the hydrogen bond and it was found that these results agree with those rendered by the crystallographic geometrical analysis, with only three exceptions, for which bond critical points were not found.

Molecular and crystalline structure of cycloheptanespiro-3'(4'H)-6',7',8',9'-tetrahydrocyclohexa[b][1,4]thiazole-2'(5'H)-thione from powder synchrotron X-ray diffraction data.

A series of bidentate nitrogen-sulfur pro-ligands has been designed and synthesized with the purpose of introducing a structural modification that favours the tetrahedral site distortions of metalloprotein systems with metallic centers surrounded by ligands containing two N atoms and two S atoms as donor groups. Some of these new pro-ligands were obtained only as powders. Here we present the molecular and crystalline structure of cycloheptanespiro-3'(4'H)-6',7',8',9'-tetrahydrocyclohexa[b][1,4]thiazole-2'(5'H)-thione (I) solved and refined from powder synchrotron X-ray diffraction data. Two independent molecules comprising a total of 36 non-H atoms were obtained from the direct-methods solution and refined against the powder X-ray diffraction data using the Rietveld method. The molecular conformations of the heterocyclic benzothiazine ring, the fused heptenyl ring and the heptanyl spiro ring are thoroughly discussed and compared with VASP theoretical calculations and other related structures. The packing of molecules in (I) is based on hydrogen bonds of the type N-H...S and hydrophobic C-H interactions.

(2S)-1-Carbamoylpyrrolidine-2-carboxylic acid.

In the title compound, also known as N-carbamoyl-L-proline, C(6)H(10)N(2)O(3), the pyrrolidine ring adopts a half-chair conformation, whereas the carboxyl group and the mean plane of the ureide group form an angle of 80.1 (2) degrees. Molecules are joined by N-H...O and O-H...O hydrogen bonds into cyclic structures with graph-set R(2)(2)(8), forming chains in the b-axis direction that are further connected via N-H...O hydrogen bonds into a three-dimensional network.

(S)-5-Benzylimidazolidine-2,4-dione monohydrate.

The crystal structure of the title compound, C(10)H(10)N(2)O(2).H(2)O, also known as L-5-benzylhydantoin monohydrate, is described in terms of two-dimensional supramolecular arrays built up from infinite chains assembled via N-H...O and O-H...O hydrogen bonds among the organic molecules and solvent water molecules, with graph-set R(3)(3)(10)C(5)C(2)(2)(6). The hydrogen-bond network is reinforced by stacking of the layers through C-H...pi interactions.

Hydrogen-bonding patterns in rac-1-acetyl-5-methyl-2-thioxoimidazolidin-4-one.

In the title compound, C(6)H(8)N(2)O(2)S, also known as N-acetyl-2-thiohydantoin-alanine, the molecules are joined by N-H...O hydrogen bonds, forming centrosymmetric R2(2)(8) dimers; these dimers are linked by C-H...O interactions to form R2(2)(10) rings, thus forming C2(2)(10) chains that run along the [101] direction.

Temperature effects on the hydrogen-bond patterns in 4-piperidinecarboxylic acid.

A temperature-controlled X-ray powder diffraction experiment, complemented with TGA and DSC analysis, allowed us to follow changes in the molecular conformation and hydrogen-bond patterns of 4-piperidinecarboxylic acid. The presence of three phases is confirmed. Phase 1 represents the monohydrated form of 4-piperidinecarboxylic acid, which exists from room temperature to 359 K, where dehydration occurs. Phase 2 measured at 363 K corresponds to an anhydrous form of the acid. At ca 458 K the onset of a second, more gradual transition is observed, which ends at around 543 K. Phase 3 measured at 543 K is a high-temperature anhydrous form of the acid. The structures of phases 2 and 3 were solved from synchrotron powder diffraction data by simulated annealing using the DASH program and refined by the Rietveld method. The phase changes are accompanied by modification of the hydrogen-bond patterns and of the torsional orientation of the terminal carboxylate group. This group makes a 49 degrees rotation about the C1-C2 bond during the first transition.

Structure of lithium benzilate hemihydrate solved by simulated annealing and difference Fourier synthesis from powder data.

The crystal structure of lithium benzilate hemihydrate (C(14)H(11)O(3)(-)Li(+).0.5H(2)O) was solved from synchrotron powder diffraction data. This compound crystallizes in the monoclinic space group P2(1)/a. The structure was solved via the direct space search for two benzilate fragments using the simulated-annealing program DASH, localization of the lithium ions and water molecule from a difference Fourier map, and a restrained Rietveld refinement (R(wp) = 0.0687). The structure is a coordination polymer of [Li(2)(C(14)H(11)O(3))(2).H(2)O](2) tetramers building helical fourfold one-dimensional channels parallel to [010]. Inside the channels the tetrahedral coordination spheres of the lithium ions contain hydroxyl and carbonyl groups, and water molecules. The water molecule functions as the cohesive entity forming extended hydrogen-bonded chains running along [010], and bifurcated donor hydrogen bonds with the two nearest carboxylates. At the outer edge of the channels, weaker intermolecular C-H.Ph hydrogen bonds along [100] and [001] contribute to the supramolecular aggregation of the structure.