Novel C3-Methylene-Bridged Indole Derivatives with and without Substituents at N1: The Influence of Substituents on Their Hemolytic, Cytoprotective, and Antimicrobial Activity.

Alkaloids are natural compounds useful as scaffolds for discovering new bioactive molecules. This study utilized alkaloid gramine to synthesize two groups of C3-substituted indole derivatives, which were either functionalized at N1 or not. The compounds were characterized by spectroscopic methods. The protective effects of the new compounds against in vitro oxidative hemolysis induced by standard oxidant 2,2'-azobis(2-amidinopropane dihydro chloride (AAPH) on human erythrocytes as a cell model were investigated. Additionally, the compounds were screened for antimicrobial activity. The results indicated that most of the indole derivatives devoid of the N1 substitution exhibited strong cytoprotective properties. The docking studies supported the affinities of selected indole-based ligands as potential antioxidants. Furthermore, the derivatives obtained exhibited potent fungicidal properties. The structures of the eight derivatives possessing indole moiety bridged to the imidazole-, benzimidazole-, thiazole-, benzothiazole-, and 5-methylbenzothiazoline-2-thiones were determined by X-ray diffraction. The C=S bond lengths in the thioamide fragment pointed to the involvement of zwitterionic structures of varying contribution. The predominance of zwitterionic mesomers may explain the lack of cytoprotective properties, while steric effects, which limit multiple the hydrogen-bond acceptor properties of a thione sulfur, seem to be responsible for the high hemolytic activity.

Synthesis, Structure and Biological Activity of Indole-Imidazole Complexes with ZnCl2: Can Coordination Enhance the Functionality of Bioactive Ligands?

The ability of the indole-imidazole hybrid ligands to coordinate with the Zn(II) ion and the resulting structures of this new class of coordination compounds were analyzed in order to determine their structural properties and biological functionalities. For this purpose, six novel Zn(II) complexes, [Zn(InIm)2Cl2] (1), [Zn(InMeIm)2Cl2] (2), [Zn(IniPrIm)2Cl2] (3), [Zn(InEtMeIm)2Cl2] (4), [Zn(InPhIm)2Cl2] (5) and [Zn2(InBzIm)2Cl2] (6) (where InIm is 3-((1H-imidazol-1-yl)methyl)-1H-indole), were synthesized by the reactions of ZnCl2 and the corresponding ligand in a 1:2 molar ratio in methanol solvent at an ambient temperature. The structural and spectral characterization of these complexes was performed using NMR, FT-IR and ESI-MS spectrometry and elemental analysis, and the crystal structures of 1-5 were determined using single-crystal X-ray diffraction. Complexes 1-5 form polar supramolecular aggregates by utilizing, for this purpose, the N-H(indole)∙∙∙Cl(chloride) intermolecular hydrogen bonds. The assemblies thus formed differ depending on the distinctive molecular shape, which can be either compact or extended. All complexes were screened for their hemolytic, cytoprotective, antifungal, and antibacterial activities. The results show that the cytoprotective activity of the indole/imidazole ligand significantly increases upon its complexation with ZnCl2 up to a value comparable with the standard antioxidant Trolox, while the response of its substituted analogues is diverse and less pronounced.

Indole Derivatives Bearing Imidazole, Benzothiazole-2-Thione or Benzoxazole-2-Thione Moieties-Synthesis, Structure and Evaluation of Their Cytoprotective, Antioxidant, Antibacterial and Fungicidal Activities.

In the search for new bioactive compounds, a methodology based on combining two molecules with biological properties into a new hybrid molecule was used to design and synthesize of a series of ten indole derivatives bearing imidazole, benzothiazole-2-thione, or benzoxazole-2-thione moieties at the C-3 position. The compounds were spectroscopically characterized and tested for their antioxidant, antibacterial, and fungicidal activities. The crystal structures were determined for five of them. Comparison of the closely related structures containing either benzothiazole-2-thione or benzoxazole-2-thione clearly shows that the replacement of -S- and -O- ring atoms modify molecular conformation in the crystal, changes intermolecular interactions, and has a severe impact on biological activity. The results indicate that indole-imidazole derivatives with alkyl substituent exhibit an excellent cytoprotective effect against AAPH-induced oxidative hemolysis and act as effective ferrous ion chelating agents. The indole-imidazole compound with chlorine atoms inhibited the growth of fungal strains: Coriolus versicolor (Cv), Poria placenta (Pp), Coniophora puteana (Cp), and Gloeophyllum trabeum (Gt). The indole-imidazole derivatives showed the highest antibacterial activity, for which the largest growth-inhibition zones were noted in M. luteus and P. fluorescens cultures. The obtained results may be helpful in the development of selective indole derivatives as effective antioxidants and/or antimicrobial agents.

One-step Access to Resorcinsalens-Solvent-Dependent Synthesis, Tautomerism, Self-sorting and Supramolecular Architectures of Chiral Polyimine Analogues of Resorcinarene.

Substituted 2,4- and 4,6-dihydroxyisophthalaldehydes were condensed with optically pure and racemic trans-1,2-diaminocyclohexane to form resorcinarene-like polyimine macrocycles (resorcinsalens), the structure and stoichiometry of which were controlled by the choice of the reaction medium. Particularly, the cyclocondensation reactions were driven by the solubility, tautomerization, or by social self-sorting. The resorcinsalens crystallized as inclusion compounds, in which the guest molecules were situated either in channels or in voids. In the highly hydrated crystals of one of the [2+2] macrocycles and chloroform-solvated crystals of a [4+4] product the channels were interconnected, as in zeolites, enabling possible migration of loosely bound solvent molecules in three dimensions. The association mode depended on the structural modification of the host molecule and the type of included solvent molecule(s).

Benzhydryl Ethers of Tartaric Acid Derivatives: Stereochemical Response of a Dynamically Chiral Propeller.

The benzhydryl (diphenylmethyl) group is a molecular propeller that can act as a chirality reporter if it is introduced nearby a stereogenic center by making an ether bond. The hydrophobic character of the benzhydryl group allows transformation of insoluble natural tartaric acid derivatives into soluble entities in a nonpolar environment. Electronic circular dichroism spectra, recorded within the short-wavelength region of the phenyl 1 B transitions (190-200 nm) shows strong bisignate Cotton effects. The signs and magnitudes of these Cotton effects are a function of absolute configuration and conformation of the molecule and do not primarily arise from exciton coupling of chiral benzhydryl chromophores. In crystals, the main-chain conformation is stabilized by intramolecular hydrogen bonds and CH-CO dipolar interactions. The number of the donor NH groups has a pronounced effect on the preferred conformations and inclusion properties of benzhydryl-(R,R)-tartaric acid diamides. Evidence is shown for the solvent dependency of the conformations of NH amides of tartaric acid diphenylmethyl ethers.

Antioxidant properties of thio-caffeine derivatives: Identification of the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine as antioxidant and highly potent cytoprotective agent.

A series of nine thio-caffeine analogues were synthesized and characterised by NMR, FT-IR and MS spectroscopic methods. Molecular structures of four of them were determined using single crystal X-ray diffraction methods. The antioxidant properties of all compounds, at concentration ranges from 0.025 to 0.1mg/mL, were evaluated by various chemical- and cell-based antioxidant assays. Human erythrocytes were used to examine in vitro haemolytic activity of all compounds and their protective effect against oxidative haemolysis induced by AAPH, one of the commonly used free radical generator. All compounds studied showed no effect on the human erythrocytes membrane structure and permeability with the exception of 8-(phenylsulfanyl)caffeine. Among the nine caffeine thio-analogues tested, the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine possessed exceptionally high antioxidant properties. Moreover, it protects human erythrocytes against AAPH-induced oxidative damage as efficiently as the standard antioxidant Trolox. Therefore, 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]caffeine may have a significant cytoprotective potential caused by its antioxidant activity.

Intramolecular interactions of trityl groups.

Trityl group, Tr, is a molecular dynamic rotor of which the conformation and helicity depend on other groups in the close vicinity. Interactions with another covalently linked Tr group and with other substituents are analyzed in terms of transfer of chirality to the trityl group. Two trityl groups in a molecule can mutually interact at a distance of two, three, or five bonds. Despite its size, a Tr group attached to a cyclohexane or cyclopentane ring through an oxygen or nitrogen atom adopts either an axial or equatorial position, depending on additional stabilizing interactions, such as hydrogen bonding.

From single molecule to crystal: mapping out the conformations of tartaric acids and their derivatives.

Stereoisomers of one of the most important organic compounds, tartaric acid, optically active and meso as well as the ester or amide derivatives, can show diverse structures related to the rotation around the three carbon-carbon bonds. This study determines the controlling factors for conformational changes of these molecules in vacuo, in solution, and in the crystalline state using DFT calculations, spectroscopic measurements, and X-ray diffraction. All structural variations can be logically accounted for by the possibility of formation and breaking of hydrogen bonds between the hydroxy or amide donors and oxygen acceptors, among these the hydrogen bonds that close five-membered rings being the most stable. These findings are useful in designing molecular and crystal structures of highly polar, polyfunctional, chiral compounds.

Solution and solid-state effects on NMR chemical shifts in sesquiterpene lactones: NMR, X-ray, and theoretical methods.

Selected guaianolide type sesquiterpene lactones were studied combining solution and solid-state NMR spectroscopy with theoretical calculations of the chemical shifts in both environments and with the X-ray data. The experimental (1)H and (13)C chemical shifts in solution were successfully reproduced by theoretical calculations (with the GIAO method and DFT B3LYP 6-31++G**) after geometry optimization (DFT B3LYP 6-31 G**) in vacuum. The GIPAW method was used for calculations of solid-state (13)C chemical shifts. The studied cases involved two polymorphs of helenalin, two pseudopolymorphs of 6α-hydroxydihydro-aromaticin and two cases of multiple asymmetric units in crystals: one in which the symmetry-independent molecules were connected by a series of hydrogen bonds (geigerinin) and the other in which the symmetry-independent molecules, deprived of any specific intermolecular interactions, differed in the conformation of the side chain (badkhysin). Geometrically different molecules present in the crystal lattices could be easily distinguished in the solid-state NMR spectra. Moreover, the experimental differences in the (13)C chemical shifts corresponding to nuclei in different polymorphs or in geometrically different molecules were nicely reproduced with the GIPAW calculations.

Synthesis, spectral and solid state characterization of a new bioactive hydrazine bridged cyclic diphosphonium compound.

The facile preparation of a racemic hydrazine bridged diphosphonium compound possessing a ring system analogous to bicyclo[3.3.2]decane is reported. Although the reaction yield is low, the structure of the compound, which possesses an eight-membered ring, two phosphonium cationic centers, a biimino bridge, molecular chirality and two fused aromatic rings locked into roughly perpendicular planes is unusual. The compound displays substantial biological activity in the brine shrimp test and cleaves plasmid DNA.

Synthesis, antioxidant and cytoprotective activity evaluation of C-3 substituted indole derivatives.

A series of fifteen indole derivatives substituted at the C-3 position were synthesized and characterized. The antioxidant activity of all derivatives was investigated by three in vitro antioxidant assays, and the derivative with pyrrolidinedithiocarbamate moiety was the most active as a radical scavenger and Fe3+-Fe2+ reducer. It can be stated that possible hydrogen and electron transfer mechanism is suggested for the quenching of the free radical. Moreover, the indolyl radical stabilization and the presence of unsubstituted indole nitrogen atom are mandatory for the observed antioxidant activity, which strongly depends on the type of the substituent directly connected to the methylene group at the C-3 position. Human red blood cells (RBC) have been used as a cell model to study derivatives interaction with the cell membrane. Haemolytic activity and RBC shape transformation were observed for certain derivatives in a concentration-dependent manner. However, most of the derivatives at sublytic concentration showed high cytoprotective activity against oxidative haemolysis induced by 2,2'-azobis(2-methylpropionamidine) dihydrochloride (AAPH). The cytoprotective properties of derivatives can be explained mostly due to their interactions with the RBC membrane components. Taking together, theoretical estimations and experimental data confirm the beneficial interactions between the selected C-3 substituted indole derivatives and the RBC membrane under oxidative stress conditions. These results encourage us to further structural optimization of C-3 substituted indole derivatives as potent antioxidant compounds.

Solid solution of two diastereomers of [3a(R,S),7a(R,S)]-3-[(1'R)-1-phenylethyl]perhydro-1,3-benzothiazol-2-iminium chloride.

A mixture of two diastereomers with the configurations (3aS,7aS,1'R) and (3aR,7aR,1'R) forms co-crystals in which there is one unique molecule in the asymmetric unit, but the molecule displays disorder which is a result of the presence of the two diastereomers at the same crystallographic site. Theoretical calculations carried out by the DFT method with the 6-311++G(2df,p) basis set allowed for the estimation of the energy difference between the two diastereomers both in the isolated and the solid state, while the natural bond orbital (NBO), Mulliken, natural population (NPA) and CHelpG analyses helped to establish the electronic structure of the thazolidin-2-imine fragment.

Crystallographic evidence of Gly-D,L-Met oxidation to its sulfoxide in the presence of gold(III): solid solution of the racemic mixture of two diastereoisomers.

Crystallographic analysis of a solid solution of two diastereoisomers, i.e. ({(1S,R)-1-carboxy-3-[(R,S)-methylsulfinyl]propyl}aminocarbonyl)methanaminium tetrachloridoaurate(III) and ({(1S,R)-1-carboxy-3-[(S,R)-methylsulfinyl]propyl}aminocarbonyl)methanaminium tetrachloridoaurate(III), (C(7)H(15)N(2)O(4)S)[AuCl(4)], has shown that in the presence of gold(III), the methionine part of the Gly-D,L-Met dipeptide is oxidized to sulfoxide, and no coordination to the Au(III) cation through the S atom of the sulfoxide is observed. In view of our observation, literature reports that methionine acts as an N,S-bidentate donor ligand forming stable gold(III) complexes require verification. Moreover, it has been demonstrated that crystallization of the oxidation product leads to a substantial 77:23 excess of both S-methionine/R-sulfoxide and R-methionine/S-sulfoxide over S-methionine/S-sulfoxide and R-methionine/R-sulfoxide. The presence of two different diastereoisomers at the same crystallographic site is a source of static disorder at this site.

Mononuclear gold(iii) complexes with diazanaphthalenes: the influence of the position of nitrogen atoms in the aromatic rings on the complex crystalline properties.

A series of mononuclear gold(iii) complexes of the general formula [AuCl3(diazanaphthalene)], where diazanaphthalene is quinazoline (qz, 1), phthalazine (phtz, 2), 1,5-naphthyridine (1,5-naph, 3), 1,6-naphthyridine (1,6-naph, 4) or 1,8-naphthyridine (1,8-naph, 5), were prepared and fully characterized. The complexes 1-5 consist of discrete monomeric species with the Au(iii) cation in a square planar coordination geometry surrounded by three chloride anions and one diazanaphthalene ligand. Crystallographic studies indicate the presence of an extended 4 + 1 or 4 + 2 geometry around the square planar [AuCl3(diazanaphthalene)] center due to Au⋯Cl and Au⋯N interactions. The crystal structures of these complexes are controlled by a variety of intermolecular interactions that utilize the amphiphilic properties of the coordinated chloride anions and involve C-H groups, π-electrons, and an uncoordinated nitrogen atom of the diazanaphthalene ligand. The usual offset π-stacking between the N-heteroaromatic ligands appears to be completely hindered between the 1,5-naph fragments and significantly weakened between the 1,6-naph and 1,8-naph in their respective complexes 3, 4 and 5, for which the average molecular polarizability (α) values are the lowest in the series. It is remarkable that the [AuCl3(benzodiazine)] complexes 1 and 2 form centrosymmetric crystals, but the [AuCl3(naphthyridine)] complexes 3-5 assemble into non-centrosymmetric aggregates, making them potential alternatives to the previously studied systems for application in various fields by taking advantage of their polarity.

Zinc(II) complexes with aromatic nitrogen-containing heterocycles as antifungal agents: Synergistic activity with clinically used drug nystatin.

Three novel Zn(II) complexes, [ZnCl2(qz)2] (1), [ZnCl2(1,5-naph)]n (2) and [ZnCl2(4,7-phen)2] (3), where qz is quinazoline, 1,5-naph is 1,5-naphthyridine and 4,7-phen is 4,7-phenanthroline, were synthesized by the reactions of ZnCl2 and the corresponding N-heterocyclic ligand in 1:2 molar ratio in ethanol at ambient temperature. The characterization of these complexes was done by NMR, IR and UV-Vis spectroscopy, and their crystal structures were determined by single-crystal X-ray diffraction analysis. Complexes 1 and 3 are mononuclear species, in which Zn(II) ion is tetrahedrally coordinated by two nitrogen atoms belonging to two qz or 4,7-phen ligands, respectively, and by two chloride anions, while complex 2 is a 1D coordination polymer that contains 1,5-naph as bridging ligand between two metal ions. In agar disc-diffusion assay, complexes 1-3 manifested good inhibitory activity against two investigated Candida strains (C. albicans and C. parapsilosis), while not inducing toxic effects on the healthy human fibroblast cell line (MRC-5). This activity was not fungicidal, as revealed by the broth microdilution assay, however complex 3 showed the ability to modulate Candida hyphae formation, which is an important process during infection and showed significant synergistic effect with clinically used antifungal polyene nystatin.

Synthesis, conformation and chiroptical properties of diaryl esters of tartaric acid.

Previously unknown diaryl esters of l-tartaric acid have been synthesized. Their conformations have been studied by DFT calculations, NMR and circular dichroism spectroscopy in solution, as well as by X-ray diffraction in the crystalline state. The four-carbon tartrate chain of diaryl esters was found to be extended in all cases, with a higher degree of nonplanarity in the crystals. Dinaphthyl tartrates show unusually strong exciton Cotton effects (A = -228 for di-1-naphthyl l-tartrate) due to the coupling of allowed 1B(b) transitions in naphthyl chromophores, despite the acyclic structure and significant distance (over 10 A) between the two chromophores.

Probing the shapes of chiral bis-(o-naphthalimidobenzoyl) systems using X-ray and circular dichroism methods.

CD (circular dichroism) and X-ray investigations have been carried out in order to identify the prevalent conformations and define the forces that determine the molecular and supramolecular organization of the alkyl-bridged bichromophoric [NAB, ortho-(1,8-naphthalimido)benzoyl] units, each consisting of the benzoyl substituted in the ortho position with the 1,8-naphthalimide group. The results reveal that NAB bichromophores incorporated into the same molecule exist in a variety of conformation/helicity combinations. The molecular structures are largely stabilized by local 1,3-CH/CO dipole-dipole interactions, while the crystal packing besides dispersive H...H interactions is mostly governed by multiple C-H...O(=C) and C-H...pi interactions. The relatively small contribution of pi...pi interactions comes from a pairwise off-face stacking between naphthalimide rings or from pairwise carbonyl...pi interactions. All these types of intermolecular interactions have been summarized quantitatively by means of a Hirshfeld surface analysis.

A three-dimensional Al(III)/Na(I) metal-organic framework resulting from dimethylformamide hydrolysis.

The three-dimensional metal-organic framework poly[bis(dimethylammonium) [hexa-mu(2)-formato-kappa(12)O:O'-aluminium(III)sodium(I)]], {(C(6)H(8)N)(2)[AlNa(HCOO)(6)]}(n), was obtained serendipitously and has been characterized by X-ray diffraction. The product has arisen as a result of a hydrolysis reaction of dimethylformamide (DMF) and contains dimethylammonium (DMA) cations included in structural voids formed by a three-dimensional [AlNa(HCOO)(6)](-) network. This study provides evidence that, in the presence of traces of aluminium, DMF stored in a glass bottle can be hydrolysed to formate and dimethylamine with simultaneous extraction of Na(+) cations from the glass. It also demonstrates that care must be taken regarding the metal and water content when DMF is not freshly distilled, since the hydrolysis of amide can occur.

Poly[[tetra-aquabis-(µ-hydroxy-acetato-κO,O:O,O)-µ(2)-sulfato-κO:O'-dicadmium(II)] monohydrate].

The title compound, {[Cd(2)(C(2)H(3)O(3))(2)(SO(4))(H(2)O)(4)]·H(2)O}(n), was obtained unintentionally in a transmetallation reaction. The crystal structure contains a two-dimensional metal-organic framework based on Cd(II)-(µ-hydroxy-acetato-κ(4)O(1),O(2):O(1),O(1'))-Cd(II) zigzag chains joined together by bridging SO(4) anions. The resulting layers are shifted with respect to each other and are stacked along the c axis. Their construction is supported by hydrogen bonds between water molecules and between water molecules and carboxylate or sulfate groups. Neighbouring layers are bridged by hydrogen bonds between the hydroxyl substituent and a sulfate anion. The sulfate anion and solvent water mol-ecule are located on twofold axes. The results demonstrate that care must be taken when preparing ethyl-enediamine-tetra-acetic acid-type complexes by transmetallation, in order to avoid precipitation of metal complexes with the α-hydroxy-acetate ligand.

Coordination behaviour and two-dimensional-network formation in poly[[mu-aqua-diaqua(mu5-propane-1,3-diyldinitrilotetraacetato)dilithium(I)cobalt(II)] dihydrate]: the first example of an M(II)-1,3-pdta complex with a monovalent metal counter-ion.

The title compound, {[CoLi2(C11H14N2O8)(H2O)3].2H2O}n, constitutes the first example of a salt of the [M(II)(1,3-pdta)](2-) complex (1,3-pdta is propane-1,3-diyldinitrilotetraacetate) with a monopositive cation as counter-ion. Insertion of the Li+ cation could only be achieved through application of the ion-exchange column technique which, however, appeared unsuccessful with other alkali metals and the ammonium cation. The structure contains two tetrahedrally coordinated Li+ cations, an octahedral [Co(1,3-pdta)](2-) anion and five water molecules, two of which are uncoordinated, and is built of two-dimensional layers extending parallel to the (010) lattice plane, the constituents of which are connected by the coordinate bonds. O-H(water)...O hydrogen bonds operate both within and between these layers. The crystal investigated belongs to the enantiomeric space group P2(1) with only one (Lambda) of two possible optical isomers of the [Co(1,3-pdta)](2-) complex. A possible cause of enantiomer separation during crystallization might be the rigidification and polarization of the [M(1,3-pdta)](2-) core, resulting from direct coordination of Li+ cations to three out of four carboxylate groups constituting the 1,3-pdta ligand. The structure of (I) differs considerably from those of the other [M(II)(1,3-pdta)](2-) complexes, in which the charge compensation is realized by means of divalent hexaaqua complex cations. This finding demonstrates a significant structure-determining role of the counter-ions.