Synthesis, Optical Characterization in Solution and Solid-State, and DFT Calculations of 3-Acetyl and 3-(1'-(2'-Phenylhydrazono)ethyl)-coumarin-(7)-substituted Derivatives.

Intramolecular charge transfer (ICT) effects are responsible for the photoluminescent properties of coumarins. Hence, optical properties with different applications can be obtained by ICT modulation. Herein, four 3-acetyl-2H-chromen-2-ones (1a-d) and their corresponding fluorescent hybrids 3- (phenylhydrazone)-chromen-2-ones (2a-d) were synthesized in 74-65% yields. The UV-Vis data were in the 295-428 nm range. The emission depends on the substituent in position C-7 bearing electron-donating groups. Compounds 1b-d showed good optical properties due to the D-π-A structural arrangement. In compounds 2a-d, there is a quenching effect of fluorescence in solution. However, in the solid, an increase is shown due to an aggregation-induced emission (AIE) effect given by the rotational restraints and stacking in the crystal. Computational calculations of the HOMO-LUMO orbitals indicate high absorbance and emission values of the molecules, and gap values represent the bathochromic effect and the electronic efficiency of the compounds. Compounds 1a-d and 2a-d are good candidates for optical applications, such as OLEDs, organic solar cells, or fluorescence markers.

Dihydropyrazole-Carbohydrazide Derivatives with Dual Activity as Antioxidant and Anti-Proliferative Drugs on Breast Cancer Targeting the HDAC6.

Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with -Br, -Cl, and -OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC50 at µM range. Compound 2b showed, in vitro, an IC50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N'-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions.

A new organic salt of metformin, an antidiabetic drug, and N,N'-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-CPMAS, thermal and BET adsorption-desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H2Mf(HpOXA)2. The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA-, as well as its structure in the solid, is herein reported for the first time. Regular O(δ-)∙∙∙C(δ), O(δ-)∙∙∙N+ and bifacial O(δ-)∙∙∙C(δ)∙∙∙O(δ-) of n→π * charge-assisted interactions are herein described in H2MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.

Crystal structure of a new polymorph of 3-acetyl-8-meth-oxy-2H-chromen-2-one.

A new polymorphic form of the title compound, C12H10O4, is described in the ortho-rhom-bic space group Pbca and Z = 8, as compared to polymorph I, which crystallizes in the monoclinic space group C2/c and Z = 8 [Li et al. (2012). Chin. J. Struct. Chem. 31, 1003-1007.]. In polymorph II, the coumarin ring system is almost planar (r.m.s. deviation = 0.00129 Å). In the crystal, mol-ecules are connected by Csp 3-H⋯O and Car-H⋯O hydrogen bonds, forming mol-ecular sheets linked into zigzag shaped layers along the b-axis direction. The three-dimensional lattice is assembled through stacking of the zigzag layers by π-π inter-actions with a centroid-to-centroid distance of 3.600 (9) Šand anti-parallel C=O⋯C=O inter-actions with a distance of 3.1986 (17) Å, which give rise to a helical supra-molecular architecture.

Crystal structure, DFT calculations and evaluation of 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione as AChE inhibitor.

Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer's disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6-H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16-H16···O3i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (- 4 0 9) and (- 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33-0.93 mM; 95% confidence interval) and has very low acute toxicity (LD50 > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use.

Solventless Synthesis of Poly(pyrazolyl)phenyl-methane Ligands and Thermal Transformation of Tris(3,5-dimethylpyrazol-1-yl)phenylmethane.

The solventless synthesis of tris(pyrazolyl)phenylmethane ligands of formula C6H5C(PzR2)3 (R = H, Me), starting from PhCCl3 and 3,5-dimethylpyrazole (PzMe2) or pyrazole (Pz) was performed. The sterically crowded C6H5C(PzMe2)3 is thermally transformed into the bis(pyrazolyl)(p-pyrazolyl)phenylmethane ligand PzMe2-C6H4CH(PzMe2)2. In this compound both PzMe2 rings are linked through the N-atom to the methine C-atom. At higher temperatures, the binding mode of PzMe2 changes from N1 to C4. All transformations occurred via quinonoid carbocation intermediates that undergo an aromatic electrophilic substitution on the 4-position of PzMe2. Reaction conditions were established to obtain five tris(pyrazolyl)phenylmethane ligands in moderate to good yields. ¹H- and 13C-NMR spectroscopy and X-ray diffraction of single crystals support the proposed structures.

Carbonyl-carbonyl interactions and amide π-stacking as the directing motifs of the supramolecular assembly of ethyl N-(2-acetylphenyl)oxalamate in a synperiplanar conformation.

The title compound, C12H13NO4, is one of the few examples that exhibits a syn conformation between the amide and ester carbonyl groups of the oxalyl group. This conformation allows the engagement of the amide H atom in an intramolecular three-centred hydrogen-bonding S(6)S(5) motif. The compound is self-assembled by C=O...C=O and amide-π interactions into stacked columns along the b-axis direction. The concurrence of both interactions seems to be responsible for stabilizing the observed syn conformation between the carbonyl groups. The second dimension, along the a-axis direction, is developed by soft C-H...O hydrogen bonding. Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory were performed to support the experimental findings.

Solid state structure and solution thermodynamics of three-centered hydrogen bonds (O∙∙∙H∙∙∙O) using N-(2-benzoyl-phenyl) oxalyl derivatives as model compounds.

Intramolecular hydrogen bond (HB) formation was analyzed in the model compounds N-(2-benzoylphenyl)acetamide, N-(2-benzoylphenyl)oxalamate and N1,N2-bis(2-benzoylphenyl)oxalamide. The formation of three-center hydrogen bonds in oxalyl derivatives was demonstrated in the solid state by the X-ray diffraction analysis of the geometric parameters associated with the molecular structures. The solvent effect on the chemical shift of H6 [δH6(DMSO-d6)-δH6(CDCl3)] and Δδ(ΝΗ)/ΔT measurements, in DMSO-d6 as solvent, have been used to establish the energetics associated with intramolecular hydrogen bonding. Two center intramolecular HB is not allowed in N-(2-benzoylphenyl)acetamide either in the solid state or in DMSO-d6 solution because of the unfavorable steric effects of the o-benzoyl group. The estimated ΔHº and ΔSº values for the hydrogen bonding disruption by DMSO-d6 of 28.3(0.1) kJ·mol-1 and 69.1(0.4) J·mol-1·K-1 for oxalamide, are in agreement with intramolecular three-center hydrogen bonding in solution. In the solid, the benzoyl group contributes to develop 1-D and 2-D crystal networks, through C-H∙∙∙A (A = O, π) and dipolar C=O∙∙∙A (A = CO, π) interactions, in oxalyl derivatives. To the best of our knowledge, this is the first example where three-center hydrogen bond is claimed to overcome steric constraints.

Helical supramolecular assembly of N2,N2')bis[3-(morpholin-4-yl)propyl]-N1,N1'-(1,2-phenylene)dioxalamide dimethyl sulfoxide monosolvate.

In the title compound, C(24)H(36)N(6)O(6)·C(2)H(6)OS, the carbonyl groups are in an antiperiplanar conformation, with O=C-C=O torsion angles of 178.59 (15) and -172.08 (16)°. An intramolecular hydrogen-bonding pattern is depicted by four N-H...O interactions, which form two adjacent S(5)S(5) motifs, and an N-H...N interaction, which forms an S(6) ring motif. Intermolecular N-H...O hydrogen bonding and C-H...O soft interactions allow the formation of a meso-helix. The title compound is the first example of a helical 1,2-phenylenedioxalamide. The oxalamide traps one molecule of dimethyl sulfoxide through N-H...O hydrogen bonding. C-H...O soft interactions give rise to the two-dimensional structure.

(E)-4-Hy-droxy-2-{[(2-phenyl-eth-yl)iminium-yl]meth-yl}phenolate.

The title Schiff base compound, C(15)H(15)NO(2), crystallized as the iminium-phenolate zwitterion. The H atom is localized on the imine N atom, forming a strong intra-molecular hydrogen bond with the phenolate O atom, and giving rise to an S(6) ring motif. The mol-ecule has an E conformation about the C=N bond. In the crystal, mol-ecules are linked by O-H⋯O hydrogen bonds, forming chains propagating along [010]. There are also C-H⋯O inter-actions present.

Synthesis and in vitro antioxidant activity evaluation of 3-carboxycoumarin derivatives and QSAR study of their DPPH• radical scavenging activity.

The in vitro antioxidant activities of eight 3-carboxycoumarin derivatives were assayed by the quantitative 1,1-diphenyl-2-picrylhydrazil (DPPH•) radical scavenging activity method. 3-Acetyl-6-hydroxy-2H-1-benzopyran-2-one (C1) and ethyl 6-hydroxy-2-oxo-2H-1-benzopyran-3-carboxylate (C2) presented the best radical-scavenging activity. A quantitative structure-activity relationship (QSAR) study was performed and correlated with the experimental DPPH• scavenging data. We used structural, geometrical, topological and quantum-chemical descriptors selected with Genetic Algorithms in order to determine which of these parameters are responsible of the observed DPPH• radical scavenging activity. We constructed a back propagation neural network with the hydrophilic factor (Hy) descriptor to generate an adequate architecture of neurons for the system description. The mathematical model showed a multiple determination coefficient of 0.9196 and a root mean squared error of 0.0851. Our results shows that the presence of hydroxyl groups on the ring structure of 3-carboxy-coumarins are correlated with the observed DPPH• radical scavenging activity effects.

N,N'-Bis(4-amino-benz-yl)oxalamide.

In the title compound, C(16)H(18)N(4)O(2), the two carbonyl groups are in an anti-periplanar conformation with an O=C-C=O torsion angle of 173.86 (17)°. In the crystal, a pair of inter-molecular N-H⋯O hydrogen bonds, forming an R(2) (2)(10) ring motif, connect the mol-ecules into an inversion dimer. The dimers are further linked by N-H⋯N and C-H⋯π inter-actions, forming a zigzag chain along the b axis.

X-ray supramolecular structure, NMR spectroscopy and synthesis of 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-ones formed by the unexpected cyclization of 3-[1-(phenyl-hydrazono)ethyl]-chromen-2-ones.

The molecular structures of nine 3-methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one isomers, obtained by the oxidative cyclization of the corresponding 1-phenylhydrazono chromen-2-ones with copper acetate as catalyst, are reported. The molecular and supramolecular structures of the 8-chloro, 8-bromo- and 8-nitro isomers 2b-d, were established by X-ray diffraction. The halogenated isomers 2b and 2c are isomorphs, they crystallize as a triclinic system, space group P-1 with two molecules in the asymmetric unit. Compound 2d crystallizes as a monoclinic system, space group P21/m with two molecules in the unit cell. The 1-phenyl ring [Cg(4)] is almost perpendicularly positioned to the chromene-pyrazole ring system. This conformation is in agreement with the anisotropic NMR shielding effect exerted by the phenyl ring over H-9 in solution. The supramolecular architecture is almost controlled by C-H···A (A = O, p) and face to face p-stacking interactions. The observed p-stacking trend between chromene and pyrazole rings is given by the overlapping between the best donor and acceptor rings in each compound.

Antioxidant activity of butyl- and phenylstannoxanes derived from 2-, 3- and 4-pyridinecarboxylic acids.

In vitro antioxidant activity for 12 stannoxanes derived from Ph(3)SnCl (compounds 1-3), Ph(2)SnCl(2) (compounds 4-6), Bu(3)SnCl (compounds 7-9), and Bu(2)SnCl(2) (compounds 10-12), was assayed qualitatively by the chromatographic profile with 1,1-diphenyl-2-picrylhydrazil (DPPH) method and by two quantitative methods: the DPPH radical scavenging activity and Ferric-Reducing Antioxidant Power (FRAP) assays. The results were compared with those obtained with the starting materials 2-pyridine- carboxylic acid (I), 3-pyridinecarboxylic acid (II) and 4-pyridinecarboxylic acid (III), as well as with standard compounds, such as vitamin C and vitamin E, respectively. The in vitro antiradical activity with DPPH of diphenyltin derivative 5 showed a very similar behavior to vitamin C at a 20 microg/mL concentration, whereas according to the FRAP method, compound 8 was better. This difference is due to the mechanism of the antioxidant process. The Structure-Activity Relationships (SAR) for both methods is also reported.

Thermal [4 + 2] cycloadditions of 3-acetyl-, 3-carbamoyl-, and 3-ethoxycarbonyl-coumarins with 2,3-dimethyl-1,3-butadiene under solventless conditions: a structural study.

The thermal [4+2] cycloadditions of 3-acetyl-, 3-carbamoyl, and 3-ethoxycarbonylcoumarins with 2,3-dimethyl-1,3-butadiene under solvent free conditions are reported, as well as the epoxidation reactions of some adducts. Discussion is focused on the structural features of the Diels-Alder adducts and their epoxides, based upon NMR, X-ray, and mass spectral data, and supported by ab initio theoretical calculations.

The zwitterion of 4-nitro-2-{(E)-[2-(piperidin-1-yl)ethyl]iminomethyl}phenol.

The title Schiff base compound, 4-nitro-1-oxo-2-{(E)-[2-(piperidin-1-yl)ethyl]iminiomethyl}cyclohexadienide, C(14)H(19)N(3)O(3), exists as a zwitterion, with the H atom of the phenol group being transferred to the imine N atom. The C=O, C(Ar)-C(Ar) and C-N bond lengths are in agreement with the oxocyclohexadienide-iminium zwitterionic form. The iminium H atom is engaged in a strong intramolecular hydrogen bond with the O atom of the keto group (N(+)-H...O) to form an S(6) motif. Soft C-H...O interactions in the ac plane lead to the development of hydrogen-bonded tapes, which are pi-stacked through the oxocyclohexadienide ring and iminium group. The significance of this study is in providing crystallographic evidence, supported by NMR and IR data, of the predominance of the oxocyclohexadienide-iminium zwitterion form over the noncharged canonical form in the title Schiff base.

Carbonyl-carbonyl, carbonyl-pi and carbonyl-halogen dipolar interactions as the directing motifs of the supramolecular structure of ethyl 6-chloro-2-oxo-2H-chromene-3-carboxylate and ethyl 6-bromo-2-oxo-2H-chromene-3-carboxylate.

The title compounds, C(12)H(9)ClO(4), (I), and C(12)H(9)BrO(4), (II), are isomorphous and crystallize in the monoclinic space group P2(1)/c. Both compounds present an anti conformation between the 3-carboxy and the lactone carbonyl groups. Both carbonyl groups are out of the plane defined by the remaining chromene atoms, by 8.37 (6) and 17.57 (6) degrees for (I), and by 9.07 (8) and 18.96 (18) degrees for (II), owing to their involvement in intermolecular interactions. In both compounds, layers of centrosymmetric hydrogen-bonded dimers are developed in the [-5 -2 22] plane through C-H...O interactions, involving both carbonyl groups as acceptors. Two families of dimers stack through C=O...C=O, C=O...pi and C-X...C=O (X = Cl and Br) dipolar interactions, as well as a C-H...pi interaction, developing the three-dimensional structure along the c axis.

Diethyl piperazine-1,4-diyldioxalate.

The ethyl oxamate group, N-C(O)-C(O)-OEt, in the title compound, alternatively called diethyl N,N':N,N'-bis(ethylene)dioxamate, C12H18N2O6, can be considered as being composed of two singly bonded amide and ester functionalities. The ethyl oxamate group is not planar. The two carbonyl groups are almost perpendicular, with an oxalyl O=C-C=O torsion angle of -111.34 (17) degrees. The molecule is located on an inversion centre. Infinite supramolecular tapes, propagating along the b axis, are formed through soft C-H...O interactions which form a centrosymmetric R(2)2(12) motif.